Author: "de Brevern Alexandre G." / Topic: [sdv.bbm] life sciences [q-bio]/biochemistry, molecular biology - Searchworks@Jio Institute Digital Library Search Results

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102 results on '"de Brevern Alexandre G."'

1. Structural variations within proteins can be as large as variations observed across their homologues

Author: Narayanaswamy Srinivasan, Bernard Offmann, Iyanar Vetrivel, Frédéric Cadet, Alexandre G. de Brevern, de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), PEACCEL, Molecular Biophysics Unit, Indian Institute of Science, Région Réunion and the Fond Social Européen, Conseil Regional des Pays de la Loire in the framework of GRIOTE project, the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Université de La Réunion, Faculty of Sciences and Technology, Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), Department of Biotechnology, Government of India, J.C. Bose National Fellow, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Structural alphabet, [SDV]Life Sciences [q-bio], Datasets as Topic, Molecular Dynamics Simulation, Molecular dynamics, Biochemistry, Mice, 03 medical and health sciences, Protein structural variation, Protein structure, Protein Domains, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Databases, Protein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Bacteria, 030102 biochemistry & molecular biology, Chemistry, Proteins, General Medicine, Protein superfamily, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Nmr data, [SDV] Life Sciences [q-bio], 030104 developmental biology, Protein conformation, Structural Homology, Protein, Structural plasticity, Biophysics
Abstract: International audience; Understanding the structural plasticity of proteins is key to understanding the intricacies of their functions and mechanistic basis. In the current study, we analyzed the available multiple crystal structures of the same protein for the structural differences. For this purpose we used an abstraction of protein structures referred as Protein Blocks (PBs) that was previously established. We also characterized the nature of the structural variations for a few proteins using molecular dynamics simulations. In both the cases, the structural variations were summarized in the form of substitution matrices of PBs. We show that certain conformational states are preferably replaced by other specific conformational states. Interestingly, these structural variations are highly similar to those previously observed across structures of homologous proteins (r 2 =0.923) or across the ensemble of conformations from NMR data (r 2 =0.919). Thus our study quantitatively shows that overall trends of structural changes in a given protein are nearly identical to the trends of structural differences that occur in the topologically equivalent positions in homologous proteins. Specific case studies are used to illustrate the nature of these structural variations.
Published: 2019

2. Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Author: Alexandre G. de Brevern, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ministry of Research (France)., University of Paris, University Paris Diderot, Sorbonne Paris Cité (France)., French National Computing Centre CINES under grant no. A0070710961 by the GENCI (Grand Equipement National de Calcul Intensif)., Conseil Régional Ile de France. INTS (SESAME Grant)., University of La Réunion, Réunion Island (France)., National Institute for Health and Medical Research (INSERM, France)., National Institute for Blood Transfusion (INTS, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: protein blocks, Protein Conformation, Computer science, Entropy, lcsh:QR1-502, Rigidity (psychology), Molecular Dynamics Simulation, Biochemistry, lcsh:Microbiology, 03 medical and health sciences, Molecular dynamics, intrinsic disorder regions, Protein structure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Statistical physics, Databases, Protein, Molecular Biology, 030304 developmental biology, Flexibility (engineering), 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Continuum (topology), Communication, protein flexibility, 030302 biochemistry & molecular biology, Atom (order theory), intrinsic disorder proteins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mobility, molecular dynamics, Characterization (materials science), Intrinsically Disordered Proteins, nuclear magnetic resonance, Order (biology), protein structures, alpha-Synuclein, X-ray structures
Abstract: International audience; Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.
Published: 2020

3. Investigating the Product Profiles and Structural Relationships of New Levansucrases with Conventional and Non-Conventional Substrates

Author: Alexandre G. de Brevern, Tarun Jairaj Narwani, Salwa Karboune, Andrea Hill, de Brevern, Alexandre G., Department of Food Science and Agricultural Chemistry [Montréal], McGill University = Université McGill [Montréal, Canada], Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Gluconobacter oxydans, Sucrose, Novosphingobium, Protein Conformation, homology modeling, Gene Expression, Oligosaccharides, Vibrio natriegens, acceptor specificity, 01 natural sciences, Quantitative Biology - Quantitative Methods, Substrate Specificity, lcsh:Chemistry, chemistry.chemical_compound, Raffinose, lcsh:QH301-705.5, Spectroscopy, Quantitative Methods (q-bio.QM), chemistry.chemical_classification, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, alcohol, Burkholderiaceae, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Recombinant Proteins, Computer Science Applications, Molecular Docking Simulation, Sphingomonadaceae, prebiotic, Protein Binding, Stereochemistry, levansucrase, Fructose, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Monosaccharide, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, fructooligosaccharide, Homology modeling, Amino Acid Sequence, Physical and Theoretical Chemistry, Molecular Biology, Vibrio, Binding Sites, 010405 organic chemistry, Organic Chemistry, Levansucrase, Biomolecules (q-bio.BM), biology.organism_classification, Acceptor, 0104 chemical sciences, Fructans, Kinetics, 030104 developmental biology, Enzyme, Prebiotics, chemistry, lcsh:Biology (General), lcsh:QD1-999, Quantitative Biology - Biomolecules, Hexosyltransferases, Structural Homology, Protein, FOS: Biological sciences, Biocatalysis, fructosylation, Sequence Alignment
Abstract: The synthesis of complex oligosaccharides is desired for their potential as prebiotics, and their role in the pharmaceutical and food industry. Levansucrase (LS, EC 2.4.1.10), a fructosyl-transferase, can catalyze the synthesis of these compounds. LS acquires a fructosyl residue from a donor molecule and performs a non-Lenoir transfer to an acceptor molecule, via &beta, (2&rarr, 6)-glycosidic linkages. Genome mining was used to uncover new LS enzymes with increased transfructosylating activity and wider acceptor promiscuity, with an initial screening revealing five LS enzymes. The product profiles and activities of these enzymes were examined after their incubation with sucrose. Alternate acceptor molecules were also incubated with the enzymes to study their consumption. LSs from Gluconobacter oxydans and Novosphingobium aromaticivorans synthesized fructooligosaccharides (FOSs) with up to 13 units in length. Alignment of their amino acid sequences and substrate docking with homology models identified structural elements causing differences in their product spectra. Raffinose, over sucrose, was the preferred donor molecule for the LS from Vibrio natriegens, N. aromaticivorans, and Paraburkolderia graminis. The LSs examined were found to have wide acceptor promiscuity, utilizing monosaccharides, disaccharides, and two alcohols to a high degree.
Published: 2020

4. Data set of intrinsically disordered proteins analysed at a local protein conformation level

Author: Melarkode Vattekatte, Akhila, Narwani, Tarun Jairaj, Floch, Aline, Maljković, Mirjana, Bisoo, Soubika, Shinada, Nicolas Ken, Kranjc, Agata, Gelly, Jean-Christophe, Srinivasan, Narayanaswamy, Mitić, Nenad, de Brevern, Alexandre, Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Belgrade [Belgrade, Serbie] (Faculty of Mathematics), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Discngine S.A.S [Paris], SBX corp, Molecular Biophysics Unit, Indian Institute of Science, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Belgrade [Belgrade], Molecular Biophysics Unit [Bangalore, India] (IISc), Indian Institute of Science [Bangalore] (IISc Bangalore), de Brevern, Alexandre G., and Univ, Réunion
Subjects: PDB, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Structural alphabet, Entropy, [SDV]Life Sciences [q-bio], Local protein conformation, lcsh:Computer applications to medicine. Medical informatics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], Biochemistry, Genetics and Molecular Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:R858-859.7, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein disorder, Ensembles, lcsh:Science (General), lcsh:Q1-390
Abstract: Intrinsic Disorder Proteins (IDPs) have become a hot topic since their characterisation in the 90s. The data presented in this article are related to our research entitled “A structural entropy index to analyse local conformations in Intrinsically Disordered Proteins” published in Journal of Structural Biology [1]. In this study, we quantified, for the first time, continuum from rigidity to flexibility and finally disorder. Non-disordered regions were also highlighted in the ensemble of disordered proteins. This work was done using the Protein Ensemble Database (PED), which is a useful database collecting series of protein structures considered as IDPs. The data set consists of a collection of cleaned protein files in classical pdb format that can be readily used as an input with most automatic analysis software. The accompanying data include the coding of all structural information in terms of a structural alphabet, namely Protein Blocks (PBs). An entropy index derived from PBs that allows apprehending the continuum between protein rigidity to flexibility to disorder is included, with information from secondary structure assignment, protein accessibility and prediction of disorder from the sequences. The data may be used for further structural bioinformatics studies of IDPs. It can also be used as a benchmark for evaluating disorder prediction methods. Keywords: Protein disorder, PDB, Ensembles, Entropy, Local protein conformation, Structural alphabet
Published: 2020

5. Discrete analysis of camelid variable domains: sequences, structures, and in-silico structure prediction

Author: Melarkode Vattekatte, Akhila, Shinada, Nicolas Ken, Narwani, Tarun, Noël, Floriane, Bertrand, Olivier, Meyniel, Jean-Philippe, Malpertuy, Alain, Gelly, Jean-Christophe, Cadet, Frédéric, de Brevern, Alexandre, de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Services and solutions for Research Informatics [Paris] (Discngine), Discngine S.A.S [Paris], Institut National de la Transfusion Sanguine [Paris] (INTS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ISoft, Atragene (Atragene), Atragene, GR-Ex, Laboratoire d'Excellence, GR-Ex, PEACCEL, Ministry of Research (France)., University Paris Diderot, Sorbonne, Paris Cité (France)., Discngine, Paris, France., ANRT, France., Conseil Régional de la Réunion., The European Social Fund EU (ESF)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., University of La Réunion, Réunion Island (France)., National Institute for Blood Transfusion (INTS, France)., National Institute for Health and Medical Research (INSERM, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV]Life Sciences [q-bio], complementarity determining regions, Bioinformatics Keywords Secondary structure, secondary structure, Subjects Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], nanobodies, [SDV] Life Sciences [q-bio], frameworks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, antibodies, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, sequence structure relationship
Abstract: International audience; Antigen binding by antibodies requires precise orientation of the complementarity- determining region (CDR) loops in the variable domain to establish the correct contact surface. Members of the family Camelidae have a modified form of immunoglobulin gamma (IgG) with only heavy chains, called Heavy Chain only Antibodies (HCAb). Antigen binding in HCAbs is mediated by only 3 CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain. This feature of the VHH, along with other important features, e.g. easy expression, small size, thermo-stability and hydrophilicity, made them promising candidates for therapeutics and diagnostics. Thus, to design better VHH domains, it is important to thoroughly understand their sequence and structure characteristics and relationships. In this study sequence, characteristics of VHH have been analysed in depth, along with their structural features using innovative approaches, namely a structural alphabet. An elaborate summary of various studies proposing structural models of VHHs showed diversity in the algorithms used. Finally, a case study to elucidate the differences in structural models from single and multiple templates is presented. In this case study, along with the above-mentioned aspects of VHH, an exciting view of various factors in structure prediction of VHH, like template framework selection, is also discussed.
Published: 2020

6. A structural entropy index to analyse local conformations in intrinsically disordered proteins: IDP PBs

Author: Melarkode Vattekatte, Akhila, Narwani, Tarun Jairaj, Floch, Aline, Maljković, Mirjana, Bisoo, Soubika, Shinada, Nicolas, Kranjc, Agata, Gelly, Jean-Christophe, Srinivasan, Narayanaswamy, Mitić, Nenad, de Brevern, Alexandre, de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Institut National de la Transfusion Sanguine [Paris] (INTS), Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Belgrade, Faculty of Mathematics, Molecular Biophysics Unit, Indian Institute of Science, Discngine S.A.S [Paris], Ministry of Research (France)., University Paris Diderot, Sorbonne, Paris Cité (France)., Discngine, Paris, France., ANRT, France., Conseil Régional de la Réunion., The European Social Fund EU (ESF)., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., Conseil Régional Ile de France. INTS (SESAME Grant)., University of La Réunion, Réunion Island (France)., National Institute for Blood Transfusion (INTS, France)., National Institute for Health and Medical Research (INSERM, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: flexibility, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], rigidity, protein structures, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, entropy, Condensed Matter::Disordered Systems and Neural Networks, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Sequence – structure – function paradigm has been revolutionized by the discovery of disordered regions and disordered proteins more than two decades ago. While the definition of rigidity is simple with X-ray structures, the notion of flexibility is linked to high experimental B-factors. The definition of disordered regions is more complex as in these same X-ray structures; it is associated to the position of missing residues. Thus a continuum so seems to exist between rigidity, flexibility and disorder. However, it had not been precisely described. In this study, we used an ensemble of disordered proteins (or regions) and, we applied a structural alphabet to analyse their local conformation. This structural alphabet, namely Protein Blocks, had been efficiently used to highlight rigid local domains within flexible regions and so discriminates deformability and mobility concepts. Using an entropy index derived from this structural alphabet, we underlined its interest to measure these local dynamics, and to quantify, for the first time, continuum states from rigidity to flexibility and finally disorder. We also highlight non-disordered regions in the ensemble of disordered proteins in our study.
Published: 2020

7. Short in-Frame Insertions/Deletions in the Coding Sequence of the α-Globin Gene. Consequences of the 3D Structure and Resulting Phenotypes: Hb Choisy as an Example

Author: Alexandre G de Brevern, Henri Wajcman, Serge Pissard, Michael C. Marden, Celine Latouche, Jean Riou, Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de génétique [CHU Mondor], CHU Henri Mondor, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and de Brevern, Alexandre G.
Subjects: hemoglobin (Hb) variant, Hemoglobins, Abnormal, [SDV]Life Sciences [q-bio], Clinical Biochemistry, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, alpha-Globins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, insertion/deletion (ins/del), Insertion deletion, Coding region, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Nucleotide, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, Genetics (clinical), Sequence (medicine), chemistry.chemical_classification, Genetics, Base Sequence, molecular modeling, Biochemistry (medical), Nucleic acid sequence, Hematology, Phenotype, Protein Structure, Tertiary, [SDV] Life Sciences [q-bio], chemistry, 030220 oncology & carcinogenesis, Hemoglobin, a-Globin, 030215 immunology
Abstract: International audience; A small group of hemoglobin (Hb) variants result from 'in-frame' deletion/insertion (del/ins). We describe a new variant of this group (Hb Choisy), found on the α1 gene, which is the exact counterpart of a previously published deletional variant, Hb J-Biskra [codons 51-58 (or codons 52-59) (-24 bp) (-TCTGCCCAGGTTAAGGGCCACGGC); HBA1: c.157_180del (or HBA2)]. In Hb J-Biskra, the sequence Ser-Ala-Gln-Val-Lys-Gly-His-Gly located from positions α52(E1) to α59(E8) is deleted, while in Hb Choisy the same sequence (Ser-Ala-Gln-Val-Lys-Gly-His-Gly) is inserted at position α52(E1). The variant carrying the insertion appears to be less damaging than the one with the deletion. A possible explanation could be that the additional sequence is located in the C to E interhelical region, and is less disturbing to the general structure of the globin chain. This insertion/deletion (ins/del) is likely favored by the repetition, at an interval of 16 nucleotides, of an eight nucleotide sequence. Comparison of variants of this group, found in the HbVar database, shows that structural modifications resulting from insertions are frequently less damaging than that caused by deletions.
Published: 2018

8. Discrete analyses of protein dynamics

Author: Vattekatte, Akhila Melarkode, Narwani, Tarun, Craveur, Pierrick, Shinada, Nicolas, Floch, Aline, Santuz, Hubert, Melarkode Vattekatte, Akhila, Srinivasan, Narayanaswamy, Rebehmed, Joseph, Gelly, Jean-Christophe, Etchebest, Catherine, De Brevern, Alexandre, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Scripps Research Institute, Discngine S.A.S [Paris], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Molecular Biophysics Unit, Indian Institute of Science, Department of Computer Science and Mathematics [Lebanese American University] (CSM/SAS/LAU), Lebanese American University (LAU), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2)., Allocation de Recherche Réunion granted by the Conseil Régional de la Réunion and the European Social Fund EU (ESF), ANRT, French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-10-CD2I-0014,NaturaDyRe,Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs(2010), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Scripps Research Institute [La Jolla, San Diego], de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Chimie Durable – Industries – Innovation - Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs - - NaturaDyRe2010 - ANR-10-CD2I-0014 - CD2I - VALID
Subjects: solvent accessibility, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Protein Conformation, Entropy, Protein Data Bank (RCSB PDB), Molecular Dynamics Simulation, Protein Structure, Secondary, 03 medical and health sciences, Molecular dynamics, Protein structure, Protein DataBank, Structural Biology, Simple (abstract algebra), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Statistical physics, Molecular Biology, Protein secondary structure, 030304 developmental biology, Physics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Entropy (statistical thermodynamics), Protein dynamics, 030302 biochemistry & molecular biology, Proteins, secondary structure, General Medicine, disorder, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], molecular dynamics, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, flexibility, structural alphabet, Macromolecule, local protein conformations
Abstract: Protein structures are highly dynamic macromolecules. This dynamics is often analysed through experimental and/or computational methods only for an isolated or a limited number of proteins. Here, we explore large-scale protein dynamics simulation to observe dynamics of local protein conformations using different perspectives. We analysed molecular dynamics to investigate protein flexibility locally, using classical approaches such as RMSf, solvent accessibility, but also innovative approaches such as local entropy. First, we focussed on classical secondary structures and analysed specifically how β-strand, β-turns, and bends evolve during molecular simulations. We underlined interesting specific bias between β-turns and bends, which are considered as the same category, while their dynamics show differences. Second, we used a structural alphabet that is able to approximate every part of the protein structures conformations, namely protein blocks (PBs) to analyse (i) how each initial local protein conformations evolve during dynamics and (ii) if some exchange can exist among these PBs. Interestingly, the results are largely complex than simple regular/rigid and coil/flexible exchange. AbbreviationsNeqnumber of equivalentPBProtein BlocksPDBProtein DataBankRMSfroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.
Published: 2019

9. Investigation of the impact of PTMs on the protein backbone conformation

Author: Tarun Jairaj Narwani, Pierrick Craveur, Alexandre G. de Brevern, Joseph Rebehmed, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), The SCRIPPS Research Institute (SCRIPPS), University of California [Los Angeles] (UCLA), University of California-University of California, Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Computer Science and Mathematics [Lebanese American University] (CSM/SAS/LAU), Lebanese American University (LAU), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2)., Calculations were also performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-10-CD2I-0014,NaturaDyRe,Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs(2010), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Chimie Durable – Industries – Innovation - Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs - - NaturaDyRe2010 - ANR-10-CD2I-0014 - CD2I - VALID, The Scripps Research Institute [La Jolla, San Diego], and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Models, Molecular, Glycosylation, Protein Conformation, Entropy, Clinical Biochemistry, N-glycosylation, Proteomics, Quantitative Biology - Quantitative Methods, Biochemistry, liver carboxylesterase, Carboxylesterase, Protein structure, N-linked glycosylation, Peptide bond, deformability, Databases, Protein, renin endopeptidase, Quantitative Methods (q-bio.QM), [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], biology, Chemistry, phosphorylation, Methylation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mobility, rigidity, statistics, Phosphorylation, actin, cyclin-dependent kinase 2 (CDK2), Computational biology, 03 medical and health sciences, Endopeptidases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Actin, 030102 biochemistry & molecular biology, Organic Chemistry, Cyclin-dependent kinase 2, Cyclin-Dependent Kinase 2, Proteins, Biomolecules (q-bio.BM), Actins, 030104 developmental biology, Quantitative Biology - Biomolecules, FOS: Biological sciences, biology.protein, methylation, Protein Processing, Post-Translational
Abstract: International audience; Post-Translational Modifications (PTMs) are known to play a critical role in the regulation of the protein functions. Their impact on protein structures, and their link to disorder regions have already been spotted on the past decade. Nonetheless, the high diversity of PTMs types, and the multiple schemes of protein modifications (multiple PTMs, of different types, at different time, etc) make difficult the direct confrontation of PTM annotations and protein structures data.We so analyzed the impact of the residue modifications on the protein structures at local level. Thanks to a dedicated structure database, namely PTM-SD, a large screen of PTMs have been done and analyze at a local protein conformation levels using the structural alphabet Protein Blocks (PBs). We investigated the relation between PTMs and the backbone conformation of modified residues, of their local environment, and at the level of the complete protein structure. The two main PTM types (N-glycosylation and phosphorylation) have been studied in non-redundant datasets, and then, 4 different proteins were focused, covering 3 types of PTMs: N-glycosylation in renin endopeptidase and liver carboxylesterase, phosphorylation in cyclin-dependent kinase 2 (CDK2), and methylation in actin. We observed that PTMs could either stabilize or destabilize the backbone structure, at a local and global scale, and that these effects depend on the PTM types.
Published: 2019

10. A minimum set of stable blocks for rational design of polypeptide chains Running head: A set of stable blocks for protein rational design

Author: Nekrasov, Alexei, Alekseeva, Ludmila, Pogosyan, Rudolf A., Dolgikh, Dmitry, Kirpichnikov, M. P., de Brevern, Alexandre, Anashkina, Anastasia, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (IBCh RAS), Russian Academy of Sciences [Moscow] (RAS), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Engelhardt Institute of Molecular Biology (ISTC), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Russian Foundation for Basic Research (#18-54-00037), Program for Molecular and Cellular Biology of the Russian Academy of Sciences, Russian Science Foundation (grant #14-14-01152), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Quantitative Biology - Biomolecules, FOS: Biological sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biomolecules (q-bio.BM), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Quantitative Biology - Quantitative Methods, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Quantitative Methods (q-bio.QM), [SDV.BIO] Life Sciences [q-bio]/Biotechnology
Abstract: International audience; The aim of this work was to find a minimal set of structurally stable pentapeptides, which allows forming a polypeptide chain of a required 3D structure. To search for factors that ensure structural stability of the pentapeptide, we generated peptide sequences with no more than three functional groups, based on the alanine pentapeptide AAAAA. We analyzed 44,860 structures of peptides by the molecular dynamics method and found that 1,225 pentapeptides over 80% of the simulation time were in a stable conformation. Clustering of these conformations revealed 54 topological types of conformationally stable pentapeptides. These conformations relate to different combined elements of the protein secondary structure. So, we obtained a minimal set of amino acid structures of conformationally stable pentapeptides, creating a complete set of different topologies that ensure the formation of pre-folded conformation of protein structures.
Published: 2019

11. Long-range molecular dynamics show that inactive forms of Protein Kinase A are more dynamic than active forms

Author: Kalaivani, R., Narwani, T. J., de Brevern, A. G., Srinivasan, N., de Brevern, Alexandre G., Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Molecular Biophysics Unit, Indian Institute of Science, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne Paris Cité (France), Fund for Improve- ment of Science and Technology infrastructure (FIST), DST, Centre for Advanced Structures (CAS), University Grants Commission (UGC), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2)., Indian Institute of Science-Department of Biotechnol- ogy partnership program, Mathematical Biology program of Department of Science and Technology, J.C. Bose National Fellow, ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: active and inactive states, structural flexibility in active and inactive state kinases, protein kinases, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Conformation, functional state, Full‐Length Papers, [SDV]Life Sciences [q-bio], Molecular Dynamics Simulation, Cyclic AMP-Dependent Protein Kinases, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], molecular dynamics, Enzyme Activation, [SDV] Life Sciences [q-bio], Mice, Catalytic Domain, STY kinases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, protein kinase A, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Phosphorylation
Abstract: International audience; Many protein kinases are characterized by at least two structural forms corresponding to the highest level of activity (active) and low or no activity, (inactive). Further, protein dynamics is an important consideration in understanding the molecular and mechanistic basis of enzyme function. In this work, we use protein kinase A (PKA) as the model system and perform microsecond range molecular dynamics (MD) simulations on six variants which differ from one another in terms of active and inactive form, with or without bound ligands, C-terminal tail and phosphorylation at the activation loop. We find that the root mean square fluctuations in the MD simulations are generally higher for the inactive forms than the active forms. This difference is statistically significant. The higher dynamics of inactive states has significant contributions from ATP binding loop, catalytic loop, and αG helix. Simulations with and without C-terminal tail show this differential dynamics as well, with lower dynamics both in the active and inactive forms if C-terminal tail is present. Similarly, the dynamics associated with the inactive form is higher irrespective of the phosphorylation status of Thr 197. A relatively stable stature of active kinases may be better suited for binding of substrates and detachment of the product. Also, phosphoryl group transfer from ATP to the phosphosite on the substrate requires precise transient coordination of chemical entities from three different molecules, which may be facilitated by the higher stability of the active state.
Published: 2019

12. Analysis of allosteric effect of pathologic variants at the light of local protein conformations

Author: de Brevern, Alexandre, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and de Brevern, Alexandre G.
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], protein structures, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, biostatistics, computer science, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, bioinformatics, entropy, long-range interactions, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], disorder proteins
Abstract: International audience; Proteins are highly dynamic macromolecules. To analyze their inherent flexibility, computational biologists often use molecular dynamics (MD) simulations. The quantification of protein flexibility is based on various methods such as Root Mean Square Fluctuations (RMSF) that rely on multiple MD snapshots or Normal Mode Analysis (NMA) that rely on a single structure and focus on quantifying large movements. Alternative in silico approaches assess protein motions through the protein residue network or dynamical correlations from MD simulations. An alternative yet powerful approach based on small prototypes or " structural alphabets " (SAs) can be used. SAs approximate conformations of protein backbones and code the local structures of proteins as one-dimensional sequences. Protein Blocks (PBs) are one of these SAs. Applying PB-based approaches to biological systems such as the DARC protein, the human αIIb β3 integrin and the KISSR1 protein highlighted the major interest of PBs in understanding local deformations of large protein structures. Specifically, these analyses have shown that a region considered as highly flexible through RMSF quantifications can be seen using PBs as locally highly rigid. This unexpected behavior is explained by a local rigidity surrounded by deformable regions. To go further, we used PBs to analyze long-range allosteric interactions in the Calf-1 domain of αIIb integrin and will also present new unpublished results. Our tool named PBxplore allows the analyses of MDs in terms of PBs and quantification with entropy index and also different types of visualization. The presentation of this research will be done in 5 successive parts: (i) the presentation and interest of the PBs, (ii) the MD of the integrins, (iii) the analysis of the results using PBs with the PBxplore software, (iv) recent developments based on PBxplore to compare reference and variant proteins, i.e. providing information about potential allosteric events and (v) the extension of the analyses to the disordered protein.
Published: 2018

13. In silico prediction of protein flexibility with local structure approach

Author: Sylvain Leonard, Pierrick Craveur, Jean-Christophe Gelly, Narayanaswamy Srinivasan, Joseph Rebehmed, Catherine Etchebest, Tarun Jairaj Narwani, Alexandre G. de Brevern, Aurélie Bornot, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Scripps Research Institute, Molecular Graphics Laboratory (MGL), Lebanese American University (LAU), Molecular Biophysics Unit, Indian Institute of Science, the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif), French National Computing Centre CINES under grant no. c2016077621 by the GENCI (Grand Equipement National de Calcul Intensif), French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and The Scripps Research Institute [La Jolla, San Diego]
Subjects: 0301 basic medicine, Bioinformatics, Protein Conformation, Datasets as Topic, Long Structural Prototypes, Molecular Dynamics Simulation, Biochemistry, Quantitative Biology - Quantitative Methods, 03 medical and health sciences, Matrix (mathematics), Structural bioinformatics, Protein structure, Protein Data Bank, evolutionary information, Support Vector Machines, Feature (machine learning), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Representation (mathematics), Databases, Protein, Quantitative Methods (q-bio.QM), protein folds, Mathematics, Flexibility (engineering), [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030102 biochemistry & molecular biology, Proteins, Biomolecules (q-bio.BM), General Medicine, computer.file_format, disorder, Structural Bioinformatics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Support vector machine, 030104 developmental biology, Quantitative Biology - Biomolecules, FOS: Biological sciences, structural alphabet, Biological system, computer, amino acid, Software
Abstract: International audience; Flexibility is an intrinsic essential feature of protein structures, directly linked to their functions. To this day, most of the prediction methods use the crystallographic data (namely B-factors) as the only indicator of protein’s inner flexibility and predicts them as rigid or flexible.PredyFlexy stands differently from other approaches as it relies on the definition of protein flexibility (i) not only taken from crystallographic data, but also (ii) from Root Mean Square Fluctuation (RMSFs) observed in Molecular Dynamics simulations. It also uses a specific representation of protein structures, named Long Structural Prototypes (LSPs). From Position-Specific Scoring Matrix, the 120 LSPs are predicted with a good accuracy and directly used to predict (i) the protein flexibility in three categories (flexible, intermediate and rigid), (ii) the normalized B-factors, (iii) the normalized RMSFs, and (iv) a confidence index. Prediction accuracy among these three classes is equivalent to the best two class prediction methods, while the normalized B-factors and normalized RMSFs have a good correlation with experimental and in silico values. Thus, PredyFlexy is a unique approach, which is of major utility for the scientific community. It support parallelization features and can be run on a local cluster using multiple cores.The entire project is available under an open-source license at http://www.dsimb.inserm.fr/~debrevern/TOOLS/predyflexy_1.3/index.php.
Published: 2018

14. On the turning away

Author: de Brevern, Alexandre, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), is work was supported by grants from the French Ministry of Research, University of Paris Diderot – Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM). AdB also acknowledges the Indo-French Centre for the Promotion of Advanced Research/CEFIPRA for collaborative grants (numbers 3903-E and 5302-2). is study was supported by grants from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. e labex GR-Ex is funded by the programme 'Investissements d’avenir' of the French National Research Agency, reference ANR-11- IDEX-0005-02. Calculations were performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant)., de Brevern, Alexandre G., and This work was supported by grants from the French Ministry of Research, University of Paris Diderot – Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM). AdB also acknowledges the Indo-French Centre for the Promotion of Advanced Research/CEFIPRA for collaborative grants (numbers 3903-E and 5302-2). is study was supported by grants from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. e labex GR-Ex is funded by the programme 'Investissements d’avenir' of the French National Research Agency, reference ANR-11- IDEX-0005-02. Calculations were performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant).
Subjects: secondary structures, propensities, structural comparison, k-means, helical structures, classification, Protein Data Bank, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, amino acid, protein folds, Self-Organizing Maps
Abstract: National audience; The functional properties of a protein depend mainly on its three-dimensional (3D) structure. They are classically assigned, visualized and analysed through the prism of classical secondary structures composed of repetitive parts (α-helices for 1/3rd of the residues and β-strands for 1/5th, resp.) connected by coil. Two other repetitive structures also exist, namely the PolyProline II and the β-turns.The β-turns have been characterized by a hydrogen bond between N-H and C=O of residues i and i+3 by Venkatachalam [1]. He also characterized the first β-turn types. Later novel turns were defined, some being discarded, leading to a final collection of type I, I’, II, II’, IV, VIa1, VIa2, VIb, and VIII β-turns. Types VIa1, VIa2 and VIb are characterized by the presence of a cis-Proline at residue i+2. Turns that do not fit any of the above criteria are classified as type IV [2].β-turn IV, i.e. the miscellaneous category, represents near 1/3rd of β-turn residues in protein structure, and is the second most frequent β -turn. 25 years have passed since the last proposition of an extension of the classical definition of β-turns. Over all we have known, it seems a good moment to dig them and to see if some new recurrent conformations are not hidden into this miscellaneous type. An automatic clustering approach based on the rules of β-turn type assignment was designed to search for recurrent new turns inside this miscellaneous type. The four most occurring clusters defined the new β-turn types. Surprisingly, these types, named IV1, IV2, IV3 and IV4, represent half of the type IV β-turns, and are more frequent that many established ones. Type IV1, is in the neighbourhood of type II but with very different amino acid composition, while IV2 is close to type VIII with related amino acid content. Types IV3 and IV4 are in the same dihedral angle region than frequent β-turn type I, but with distinct dihedral angle values [3].[1] Venkatachalam CM (1968) Stereochemical criteria for polypeptides and proteins. V. Conformation of a system of three linked peptide units. Biopolymers 6:1425-1436.[2] Hutchinson EG, Thornton JM (1996) PROMOTIF--a program to identify and analyze structural motifs in proteins. Protein Sci 5:212-220.[3] de Brevern AG (2016) Extension of the classical classification of β-turns. Sci Rep. 2016 Sep 15;6:33191.
Published: 2017

15. Dynamics and deformability of α-, 310- and π-helices

Author: Tarun Jairaj Narwani, Alexandre G. de Brevern, Catherine Etchebest, Joseph Rebehmed, Nicolas K. Shinada, Pierrick Craveur, Hubert Santuz, Université Paris-Sorbonne (UP4), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Services and solutions for Research Informatics [Paris] (Discngine), Discngine S.A.S [Paris], Department of Integrative Structural and Computational Biology [La Jolla, CA, USA], The Scripps Research Institute [La Jolla, San Diego], Department of Computer Science and Mathematics [Lebanese American University] (CSM/SAS/LAU), Lebanese American University (LAU), This work was supported by grants from the Ministry of Research (France), University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France) and labex GR-Ex. The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program 'Investissements d’avenir' of the French National Research Agency, reference ANR-11-IDEX-0005-02. TN and AdB acknowledge to Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2). This work is supported by a grant from the French National Research Agency (ANR): NaturaDyRe (ANR-2010-CD2I-014-04) to JR and AdB. NSh acknowledges support from ANRT.The authors were granted access to high performance computing (HPC) resources at the French National Computing Centre CINES under grant no. c2013037147 funded by the GENCI (Grand Equipement National de Calcul Intensif). Calculations were also performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant)., de Brevern, Alexandre G., Scripps Research Institute, and This work was supported by grants from the Ministry of Research (France), University Paris Diderot, Sorbonne, Paris Cité (France), the National Institute for Blood Transfusion (INTS, France), the National Institute for Health and Medical Research (INSERM, France) and Labex GR-Ex. The Labex GR-Ex reference ANR-11-LABX-0051 is funded by the program 'Investissements d’avenir' of the French National Research Agency, reference ANR-11- IDEX-0005-02. TN and AdB acknowledge the Indo-French Center for the Promotion of Advanced Research/CEFIPRA for the Collaborative Grant No. 5302-2. This work was supported by a grant from the French National Research Agency (ANR): NaturaDyRe (ANR-2010-CD2I-014-04) to JR and AdB. NSh acknowledges the support from ANRT. The authors were granted access to high performance computing (HPC) resources at the French National Computing Centre CINES under Grant No. c2013037147 funded by the GENCI (Grand Equipement National de Calcul Intensif). Calculations were also performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant).
Subjects: 0301 basic medicine, Flexibility (anatomy), Protein domain, General Biochemistry, Genetics and Molecular Biology, flexibility, Root mean square, 03 medical and health sciences, Molecular dynamics, Protein structure, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein secondary structure, lcsh:QH301-705.5, Helix, Chemistry, helical local conformations, disorder, molecular dynamics, Crystallography, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), structural alphabet, General Agricultural and Biological Sciences, Macromolecule, DSSP (hydrogen bond estimation algorithm)
Abstract: International audience; Protein structures are often represented as seen in crystals as (i) rigid macromolecules (ii) with helices, sheets and coils. However, both definitions are partial because (i) proteins are highly dynamic macromolecules and (ii) the description of protein structures could be more precise. With regard to these two points, we analyzed and quantified the stability of helices by considering α-helices as well as 310-and π-helices. Molecular dynamic (MD) simulations were performed on a large set of 169 representative protein domains. The local protein conformations were followed during each simulation and analyzed. The classical flexibility index (B-factor) was confronted with the MD root mean square flexibility (RMSF) index. Helical regions were classified according to their level of helicity from high to none. For the first time, a precise quantification showed the percentage of rigid and flexible helices that underlie unexpected behaviors. Only 76.4% of the residues associated with α-helices retain the conformation, while this tendency drops to 40.5% for 310-helices and is never observed for π-helices. α-helix residues that do not remain as an α-helix have a higher tendency to assume β-turn conformations than 310-or π-helices. The 310-helices that switch to the α-helix conformation have a higher B-factor and RMSF values than the average 310-helix but are associated with a lower accessibility. Rare π-helices assume a β-turn, bend and coil conformations, but not α-or 310-helices. The view on π-helices drastically changes with the new DSSP (Dictionary of Secondary Structure of Proteins) assignment approach, leading to behavior similar to 310-helices, thus underlining the importance of secondary structure assignment methods.
Published: 2017

16. Recent advances on polyproline II

Author: Alexandre G. de Brevern, Nicolas K. Shinada, Tarun Jairaj Narwani, Narayanasamy Srinivasan, Akhila Melarkode Vattekatte, Jean-Christophe Gelly, Yassine Ghouzam, Hubert Santuz, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Discngine, SAS, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Molecular Biophysics Unit, Indian Institute of Sciences (MBU), Indian Institute of Science [Bangalore] (IISc Bangalore), Grants from the Ministry of Research (France), University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France) and labex GR-Ex. The labex GR-Ex, reference ANR-11-LABX-0051 is funded by the program 'Investissements d’avenir' of the French National Research Agency, reference ANR-11-IDEX-0005-02. TjrN, NSr and AdB acknowledge to Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2). NSh acknowledges support from ANRT., and de Brevern, Alexandre G.
Subjects: 0301 basic medicine, Models, Molecular, Globular protein, Stereochemistry, Structural alphabet, Clinical Biochemistry, Computational biology, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, Protein structure, Secondary structure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein secondary structure, Region analysis, Polyproline helix, chemistry.chemical_classification, 030102 biochemistry & molecular biology, Frameworks, Chemistry, Protein dynamics, Organic Chemistry, Structure and function, 030104 developmental biology, Helix, Sequence structure relationship, Peptides, Local protein conformations
Abstract: International audience; About half of the globular proteins are composed of regular secondary structures, α-helices, and β-sheets, while the rest are constituted of irregular secondary structures, such as turns or coil conformations. Other regular secondary structures are often ignored, despite their importance in biological processes. Among such structures, the polyproline II helix (PPII) has interesting behaviours. PPIIs are not usually associated with conventional stabilizing interactions, and recent studies have observed that PPIIs are more frequent than anticipated. In addition, it is suggested that they may have an important functional role, particularly in protein-protein or protein-nucleic acid interactions and recognition. Residues associated with PPII conformations represent nearly 5% of the total residues, but the lack of PPII assignment approaches prevents their systematic analysis. This short review will present current knowledge and recent research in PPII area. In a first step, the different methodologies able to assign PPII are presented. In the second step, recent studies that have shown new perspectives in PPII analysis in terms of structure and function are underlined with three cases: (1) PPII in protein structures. For instance, the first crystal structure of an oligoproline adopting an all-trans polyproline II (PPII) helix had been presented; (2) the involvement of PPII in different diseases and drug designs; and (3) an interesting extension of PPII study in the protein dynamics. For instance, PPIIs are often linked to disorder region analysis and the precise analysis of a potential PPII helix in hypogonadism shows unanticipated PPII formations in the patient mutation, while it is not observed in the wild-type form of KISSR1 protein.
Published: 2017

17. Bioinformatic analysis of the protein/DNA interface

Author: Daniel Svozil, Jiří Černý, Bohdan Schneider, Alexandre G. de Brevern, Agnel Praveen Joseph, Jean-Christophe Gelly, de Brevern, Alexandre G., Institute of Biotechnology AS CR, Laboratory of Informatics and Chemistry, Institute of Chemical Technology [Prague] (ICT), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Czech-France collaboration Barrande [MEB021032], BIOCEV CZ.1.05/1.1.00/02.0109 from the ERDF, [P305/ 80 12/1801] from the Czech Science Foundation, and institutional [AV0Z50520701], supported by [MSM 6046137302 to D.S. and P.Č.], and supported by the Ministry of Research (France), University Paris Diderot, Sorbonne Paris Cité (France), National Institute of Blood Transfusion (INTS, France), National Institute of Health and Medical Research (INSERM, France) and 'Investissements d'avenir', Laboratories of Excellence GR-Ex (France) (to J.C.G. and A.G.dB.). Funding for open access charge: Czech Science Foundation and Academy of Sciences of the Czech Republic.
Subjects: Models, Molecular, Protein Conformation, DNA interface, Crystal structure, Plasma protein binding, Pentapeptide repeat, chemistry.chemical_compound, 0302 clinical medicine, structural alphabet: Protein Blocks, MESH: Protein Conformation, Protein structure, Structural Biology, Structural motif, Conformational isomerism, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: DNA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], DNA-Binding Proteins, MESH: Nucleic Acid Conformation, Naked DNA, Data Interpretation, Statistical, MESH: Phosphates, MESH: Models, Molecular, Protein Binding, MESH: Computational Biology, Stereochemistry, Biophysics, Biology, DNA-binding protein, Phosphates, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Water, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Transcription factor, 030304 developmental biology, Computational Biology, Water, DNA structure, DNA, Base (topology), Crystallography, chemistry, protein structures, Nucleic acid, Nucleic Acid Conformation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA interactions, protein, MESH: Data Interpretation, Statistical, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: Despite extensive studies of the geometry of protein/DNA interfaces the understanding of the affinity and specificity of the protein/DNA interactions remains elusive. We present a novel approach to geometric analysis of protein/nucleic acid interfaces that is based on classification of their local conformations. Protein structures are divided into a series of pentapeptide fragments and each is assigned one of 16 conformers or ‘protein blocks’ [de Brevern et al. Proteins 41, 271 (2000)]. Similarly, each DNA step (unit [base]sugar-phosphate-sugar[base]) is assigned one of ∼20 DNA conformers [Svozil et al. NAR 36, 3690 (2008)]. Significantly, local structures classified into distinct conformers can be represented by symbols so that they can be analyzed more easily than complicated 3D objects. Size of the fragments used for the classification allows analysis of structural features of the interface at a scale intermediate between too detailed interatomic contacts on one side and too crude protein motifs (helix-turn-helix, Zn-finger, ...) on the other. We will present correlations between protein and DNA conformers at their interface from more than 15 hundred protein/DNA crystal structures broken by various criteria of the analyzed structures as protein functional classification, e.g. in GO or Pfam or by crystallographic properties, resolution or overall structure quality.Acknowledgments. This work was supported by Czech-France collaboration Barrande (MEB021032) and Czech Science Foundation (P305/10/2184).
Published: 2013

18. Understanding the role of domain–domain linkers in the spatial orientation of domains in multi-domain proteins

Author: Alexandre G. de Brevern, Ramachandra M. Bhaskara, Narayanaswamy Srinivasan, de Brevern, Alexandre G., Molecular Biophysics Unit, Indian Institute of Science, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Indo-French collaborative grant (CEFIPRA/IFCPAR 3903-E) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) Department of Biotechnology (India)
Subjects: Models, Molecular, Protein Conformation, Interface (Java), 030303 biophysics, linker flexibility, Sequence (biology), Biochemistry, Local structure, Domain (software engineering), 03 medical and health sciences, Structural Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Computer Simulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, interface constraints, multi-domain proteins, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, Flexibility (engineering), 0303 health sciences, Binding Sites, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Orientation (computer vision), Chemistry, Proteins, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Structure, Tertiary, Multi domain, Crystallography, inter-domain orientation, inter-domain linkers, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biological system, Linker, Algorithms, Protein Binding
Abstract: International audience; Inter-domain linkers (IDLs)' bridge flanking domains and support inter-domain communication in multi-domain proteins. Their sequence and conformational preferences enable them to carry out varied functions. They also provide sufficient flexibility to facilitate domain motions and, in conjunction with the interacting interfaces, they also regulate the inter-domain geometry (IDG). In spite of the basic intuitive understanding of the inter-domain orientations with respect to linker conformations and interfaces, we still do not entirely understand the precise relationship among the three. We show that IDG is evolutionarily well conserved and is constrained by the domain-domain interface interactions. The IDLs modulate the interactions by varying their lengths, conformations and local structure, thereby affecting the overall IDG. Results of our analysis provide guidelines in modelling of multi-domain proteins from the tertiary structures of constituent domain components.
Published: 2013

19. Global analysis of VHHs framework regions with a structural alphabet

Author: Noël, Floriane, Malpertuy, Alain, de Brevern, Alexandre, de Brevern, Alexandre G., Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Atragene Informatics, and This work was supported by grants from the French Ministry of Research, University Paris Diderot, Sorbonne Paris Cité, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM). AdB also acknowledges the Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grants (numbers 5302-2). This study was supported by grants from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. The labex GR-Ex is funded by the programme 'Investissements d’avenir' of the French National Research Agency, reference ANR-11-IDEX-0005-02. Calculations were performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant).
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: secondary structure, sequence structure relationship, structural alphabet, antibodies, frameworks, VHHs, nanobodies, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; The VHHs are antigen-binding region/domain of camelid heavy chain antibodies (HCAb). They have many interesting biotechnological and biomedical properties due to their small size, high solubility and stability, and high affinity and specificity for their antigens. HCAb and classical IgGs are evolutionary related and share a common fold. VHHs are composed of regions considered as constant, called the frameworks (FRs) connected by Complementarity Determining Regions (CDRs), a highly variable region that provide interaction with the epitope. Actually, no systematic structural analyses had been performed on VHH structures despite a significant number of structures. This work is the first study to analyse the structural diversity of FRs of VHHs. Using a structural alphabet that allows approximating the local conformation, we show that each of the four FRs do not have a unique structure but exhibit many structural variant patterns. Moreover, no direct simple link between the local conformational change and amino acid composition can be detected. These results indicate that long-range interactions affect the local conformation of FRs and impact the building of structural models.
Published: 2016

20. Extension of the classical classification of β-turns: new turns

Author: de Brevern, Alexandre, de Brevern, Alexandre G., Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and This work was supported by grants from the French Ministry of Research, University of Paris Diderot – Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM). AdB also acknowledges the Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grants (numbers 3903-E and 5302-2). This study was supported by grants from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. The labex GR-Ex is funded by the programme 'Investissements d’avenir' of the French National Research Agency, reference ANR-11-IDEX-0005-02. Calculations were performed on an SGI cluster granted by Conseil Régional Ile de France and INTS (SESAME Grant).
Subjects: secondary structures, amino acids, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], propensities, k-means, [SDV]Life Sciences [q-bio], structural comparison, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV] Life Sciences [q-bio], classification, helical structures, Protein Data Bank, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein folds, Self-Organizing Maps
Abstract: International audience; The functional properties of a protein primarily depend on its three-dimensional (3D) structure. These properties have classically been assigned, visualized and analysed on the basis of protein secondary structures. The β-turn is the third most important secondary structure after helices and β-strands. β-turns have been classified according to the values of the dihedral angles φ and ψ of the central residue. Conventionally, eight different types of β-turns have been defined, whereas those that cannot be defined are classified as type IV β-turns.This classification remains the most widely used. Nonetheless, the miscellaneous type IV β-turns represent 1/3rd of β-turn residues. An unsupervised specific clustering approach was designed to search for recurrent new turns in the type IV category. The classical rules of β-turn type assignment were central to the approach. The four most frequently occurring clusters defined the new β-turn types. Unexpectedly, these types, designated IV1, IV2, IV3 and IV4, represent half of the type IV β-turns and occur more frequently than many of the previously established types. These types show convincing particularities, in terms of both structures and sequences that allow for the classical β-turn classification to be extended for the first time in 25 years.
Published: 2016

21. Protein Local Conformations at the Light of a Structural Alphabet

Author: G Alexandre, de Brevern, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and de Brevern, Alexandre G.
Subjects: 0301 basic medicine, Combinatorics, 03 medical and health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030104 developmental biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biophysics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Structural alphabet, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Mathematics
Abstract: International audience; Protein structures are classically described in terms of secondary structures. Even if the regular secondary structures have relevant physical meaning, their recognition from atomic coordinates has some important limitations such as uncertainties in the assignment of boundaries of helical and β-strand regions. Further, on an average about 50% of all residues are assigned to an irregular state, i.e., the coil. Thus different research teams have focused on abstracting conformation of protein backbone in the localized short stretches. Using different geometric measures, local stretches in protein structures are clustered in a chosen number of states. A prototype representative of the local structures in each cluster is generally defined. These libraries of local structures prototypes are named as "structural alphabets". We have developed a structural alphabet, named Protein Blocks, not only to approximate the protein structure, but also to predict them from sequence [1,2]. Since its development, we and other teams have explored numerous new research fields using this structural alphabet. I will review here some of the most interesting applications: (i) the most efficient protein superimposition methods [3,4], (ii) new ways to analyze protein structures [2], and (iii) new tool for analysis of protein dynamics and allostery [5,6].
Published: 2018

22. Protein Peeling 2: a web server to convert protein structures into series of protein units

Author: S. Hazout, A.G. de Brevern, Jean-Christophe Gelly, Catherine Etchebest, Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and de Brevern, Alexandre G.
Subjects: Protein Folding, Web server, Protein Conformation, MESH: Protein Folding, 030303 biophysics, Protein domain, Biology, computer.software_genre, Intermediate level, Bioinformatics, Article, Computational science, User-Computer Interface, MESH: Software, 03 medical and health sciences, MESH: Protein Conformation, Protein structure, Software, Computer Graphics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: User-Computer Interface, 030304 developmental biology, Internet, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Series (mathematics), business.industry, Proteins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Identification (information), MESH: Internet, Protein folding, MESH: Computer Graphics, business, computer
Abstract: Protein Peeling 2 (PP2) is a web server for the automatic identification of protein units (PUs) given the 3D coordinates of a protein. PUs are an intermediate level of protein structure description between protein domains and secondary structures. It is a new tool to better understand and analyze the organization of protein structures. PP2 uses only the matrices of protein contact probabilities and cuts the protein structures optimally using Matthews' coefficient correlation. An index assesses the compactness quality of each PU. Results are given both textually and graphically using JMol and PyMol softwares. The server can be accessed from http://www.ebgm.jussieu.fr/~gelly/index.html.
Published: 2006

23. Protein Block Expert (PBE): a web-based protein structure analysis server using a structural alphabet

Author: Manoj Tyagi, Frédéric Cadet, Bernard Offmann, A.G. de Brevern, C. S. Swamy, P. Sharma, Narayanaswamy Srinivasan, de Brevern, Alexandre G., Laboratoire de Biochimie et Génétique Moléculaire (LBGM), Université de La Réunion (UR), Molecular Biophysics Unit, Indian Institute of Science, Bioinformatique génomique et moléculaire ((U 726)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Protein structure database, MESH: Databases, Protein, Protein Folding, MESH: Sequence Analysis, Protein, Protein Conformation, MESH: Protein Folding, Structural alignment, Amino Acid Motifs, MESH: Sequence Alignment, Sequence alignment, Biology, Bioinformatics, Substitution matrix, Article, 03 medical and health sciences, MESH: Amino Acid Motifs, MESH: Software, User-Computer Interface, Protein structure, MESH: Protein Conformation, Protein methods, Sequence Analysis, Protein, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Databases, Protein, 030304 developmental biology, MESH: User-Computer Interface, 0303 health sciences, Internet, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030302 biochemistry & molecular biology, String (computer science), Structural Classification of Proteins database, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Internet, Algorithm, Sequence Alignment, Software
Abstract: Encoding protein 3D structures into 1D string using short structural prototypes or structural alphabets opens a new front for structure comparison and analysis. Using the well-documented 16 motifs of Protein Blocks (PBs) as structural alphabet, we have developed a methodology to compare protein structures that are encoded as sequences of PBs by aligning them using dynamic programming which uses a substitution matrix for PBs. This methodology is implemented in the applications available in Protein Block Expert (PBE) server. PBE addresses common issues in the field of protein structure analysis such as comparison of proteins structures and identification of protein structures in structural databanks that resemble a given structure. PBE-T provides facility to transform any PDB file into sequences of PBs. PBE-ALIGNc performs comparison of two protein structures based on the alignment of their corresponding PB sequences. PBE-ALIGNm is a facility for mining SCOP database for similar structures based on the alignment of PBs. Besides, PBE provides an interface to a database (PBE-SAdb) of preprocessed PB sequences from SCOP culled at 95% and of all-against-all pairwise PB alignments at family and superfamily levels. PBE server is freely available at http://bioinformatics.univ-reunion.fr/PBE/.
Published: 2006

24. mulPBA: an efficient multiple protein structure alignment method based on a structural alphabet

Author: Alexandre G. de Brevern, Sylvain Leonard, Agnel Praveen Joseph, Jean-Christophe Gelly, Narayanaswamy Srinivasan, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), GR-Ex, Laboratoire d'Excellence, GR-Ex, Molecular Biophysics Unit, Indian Institute of Science, Indo-French collaborative grant (CEFIPRA/IFCPAR 3903-E) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) Department of Biotechnology (India), and de Brevern, Alexandre G.
Subjects: Models, Molecular, Web server, Protein Conformation, Computer science, Structural alignment, MESH: Sequence Alignment, computer.software_genre, webserver, 03 medical and health sciences, MESH: Software, MESH: Protein Conformation, Structural Biology, Iterative refinement, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Loop modeling, protein conformations, protein superimposition, Molecular Biology, Java applet, 030304 developmental biology, Internet, 0303 health sciences, Multiple sequence alignment, 030302 biochemistry & molecular biology, Computational Biology, Proteins, General Medicine, computer.file_format, Protein structure prediction, Protein Data Bank, Crystallography, MESH: Internet, protein structures, Protein Blocks, structural alphabet, Sequence Alignment, computer, Algorithm, Software, MESH: Models, Molecular, MESH: Computational Biology
Abstract: International audience; The increasing number of available protein structures requires efficient tools for multiple structure comparison. Indeed, multiple structural alignments are essential for the analysis of function, evolution and architecture of protein structures. For this purpose, we proposed a new web server called multiple Protein Block Alignment (mulPBA). This server implements a method based on a structural alphabet to describe the backbone conformation of a protein chain in terms of dihedral angles. This 'sequence-like' representation enables the use of powerful sequence alignment methods for primary structure comparison, followed by an iterative refinement of the structural superposition. This approach yields alignments superior to most of the rigid-body alignment methods and highly comparable with the flexible structure comparison approaches. We implement this method in a web server designed to do multiple structure superimpositions from a set of structures given by the user. Outputs are given as both sequence alignment and superposed 3D structures visualized directly by static images generated by PyMol or through a Jmol applet allowing dynamic interaction. Multiple global quality measures are given. Relatedness between structures is indicated by a distance dendogram. Superimposed structures in PDB format can be also downloaded, and the results are quickly obtained. mulPBA server can be accessed at www.dsimb.inserm.fr/dsimb_tools/mulpba/ .
Published: 2014

25. Correlation between local structural dynamics of proteins inferred from NMR ensembles and evolutionary dynamics of homologues of known structure.: Inherent and evolutionary structural dynamics

Author: Mahajan, Swapnil, de Brevern, Alexandre, Offmann, Bernard, Srinivasan, Narayanaswamy, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), GR-Ex, Laboratoire d'Excellence, GR-Ex, Université de La Réunion - Faculté des Sciences et Technologies (FST), Université de La Réunion (UR), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), MBU, Molecular Biophysics Unit, Indian Institute of Science-Indian Institute of Science, SM is supported by PhD scholarship grant from Fonds Européen de Dévelopment Régional and Conseil Regional de La Réunion [20100079, Tiers: 144645]. This research is also supported by Indo-French collaborative grant (CEFIPRA/IFCPAR 3903-E) to NS and AdB. This work was supported by grants from the Ministry of Research (France), University of Paris Diderot, Sorbonne Paris Cité (France), National Institute for Blood Transfusion (INTS, France), Institute for Health and Medical Research (INSERM, France) to AdB, University of Nantes (France) and Conseil Régional Pays de La Loire (France) to BO and Department of Biotechnology (India) to NS., and de Brevern, Alexandre G.
Subjects: Quantitative Biology::Biomolecules, substitution matrix, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], structural variation, conservation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], NMR, flexibility, statistics, evolution, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; Conformational changes in proteins are extremely important for their biochemical functions. Correlation between inherent conformational variations in a protein and conformational differences in its homologues of known structure is still unclear. In this study, we have used a structural alphabet called Protein Blocks (PBs). PBs are used to perform abstraction of protein 3-D structures into a 1-D strings of 16 alphabets (a-p) based on dihedral angles of overlapping pentapeptides. We have analyzed the variations in local conformations in terms of PBs represented in the ensembles of 801 protein structures determined using NMR spectroscopy. In the analysis of concatenated data over all the residues in all the NMR ensembles, we observe that the overall nature of inherent local structural variations in NMR ensembles is similar to the nature of local structural differences in homologous proteins with a high correlation coefficient of .94. High correlation at the alignment positions corresponding to helical and β-sheet regions is only expected. However, the correlation coefficient by considering only the loop regions is also quite high (.91). Surprisingly, segregated position-wise analysis shows that this high correlation does not hold true to loop regions at the structurally equivalent positions in NMR ensembles and their homologues of known structure. This suggests that the general nature of local structural changes is unique; however most of the local structural variations in loop regions of NMR ensembles do not correlate to their local structural differences at structurally equivalent positions in homologues.
Published: 2014

26. β-Bulges: extensive structural analyses of β-sheets irregularities

Author: Craveur, Pierrick, Joseph, Agnel Praveen, Rebehmed, Joseph, De Brevern, Alexandre, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), The Ministry of Research (France), The University Paris Diderot, Sorbonne Paris Cite (France), The National Institute of Blood Transfusion (INTS, France), The National Institute of Health and Medical Research (INSERM, France), The Laboratories of Excellence, GR-Ex (France), HFSP (India), NCBS (India), and de Brevern, Alexandre G.
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Conformation, Molecular Sequence Data, Proteins, Hydrogen Bonding, Articles, bioinformatics, Molecular Dynamics Simulation, sequence, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Structure, Secondary, protein aggregation, Evolution, Molecular, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Amino Acids, protein structure, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], structure relationship, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; β-Sheets are quite frequent in protein structures and are stabilized by regular main-chain hydrogen bond patterns. Irregularities in β-sheets, named β-bulges, are distorted regions between two consecutive hydrogen bonds. They disrupt the classical alternation of side chain direction and can alter the directionality of β-strands. They are implicated in protein-protein interactions and are introduced to avoid β-strand aggregation. Five different types of β-bulges are defined. Previous studies on β-bulges were performed on a limited number of protein structures or one specific family. These studies evoked a potential conservation during evolution. In this work, we analyze the β-bulge distribution and conservation in terms of local backbone conformations and amino acid composition. Our dataset consists of 66 times more β-bulges than the last systematic study (Chan et al. Protein Science 1993, 2:1574-1590). Novel amino acid preferences are underlined and local structure conformations are highlighted by the use of a structural alphabet. We observed that β-bulges are preferably localized at the N- and C-termini of β-strands, but contrary to the earlier studies, no significant conservation of β-bulges was observed among structural homologues. Displacement of β-bulges along the sequence was also investigated by Molecular Dynamics simulations.
Published: 2013

27. Evolution study of the Baeyer-Villiger monooxygenases enzyme family: functional importance of the highly conserved residues

Author: Véronique de Berardinis, Véronique Alphand, Alexandre G. de Brevern, Joseph Rebehmed, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The National Center for Atomic Research (CEA,France) University d'Aix-Marseille (France) The National Center for Scientific Research (CNRS,France) high performance computing (HPC) resources at the French National Computing Center CINES under grant no. 2012-c2012076930 funded by the GENCI (Grand Equipement National de Calcul Intensif)., Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and de Brevern, Alexandre G.
Subjects: Threonine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, ketones, phylogeny, 01 natural sciences, Biochemistry, Conserved sequence, Mixed Function Oxygenases, Protein structure, esters, Rhodococcus, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, lactones, Conserved Sequence, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], chemistry.chemical_classification, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, enentioselectivity, [CHIM.CATA] Chemical Sciences/Catalysis, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Amino acid, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, sequence alignment, Flavin-Adenine Dinucleotide, Stereochemistry, Sequence alignment, Biology, 010402 general chemistry, stereoselectivity, 03 medical and health sciences, Pseudomonas, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure, 030304 developmental biology, function, Binding Sites, [CHIM.CATA]Chemical Sciences/Catalysis, Monooxygenase, interactions, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Enzyme binding, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Function (biology), NADP
Abstract: International audience; Baeyer-Villiger monooxygenases (BVMOs) catalyze the transformation of linear and cyclic ketones into their corresponding esters and lactones by introducing an oxygen atom into a C-C bond. This bioreaction has numerous advantages compared to its chemical version; it does not induce the use of potentially harmful reagents (i.e., green chemistry) and displays significant better enantio- and regio-selectivity. New potential BVMOs were searched using sequence homology for type I BVMO proteins. 116 new sequences were identified as new putative BVMOs respecting the defined selection criteria. Multiple sequence alignments were carried out on the selected sequences to study the conservation of structurally and/or functionally important amino acids during evolution. Type I BVMO signature motif was found to be conserved in 94.8% of the sequences. We noticed also the highly conserved - but previously unnoticed - Threonine 167 (93.1%), located in the signature motif; this position could be added in the pattern used to characterize specific Type I enzymes. Amino acids at the vicinity of the FAD and NADPH cofactors were found also to be highly conserved and the details of the interactions were emphasized. Interestingly, residues at the enzyme binding site were found less conserved in terms of sequence evolution, leading sometimes to some important amino acid changes. These behaviors could explain the enzyme selectivity and specificity for different ligands.
Published: 2013

28. VLDP web server: a powerful geometric tool for analysing protein structures in their environment

Author: Alexandre G. de Brevern, Jeremy Esque, Sylvain Leonard, Christophe Oguey, Laboratoire de Physique Théorique et Modélisation (LPTM - UMR 8089), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The University of Cergy-Pontoise (France) The National Center for Scientific Research (CNRS,France), de Brevern, Alexandre G., and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)
Subjects: Models, Molecular, Web server, MESH: Amino Acids, Protein Conformation, Voronoi, protein accessibility, Biology, Bioinformatics, computer.software_genre, 01 natural sciences, tessellations, Set (abstract data type), 03 medical and health sciences, MESH: Software, Protein structure, MESH: Protein Conformation, 0103 physical sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, Delaunay, Internet, 0303 health sciences, amino acids, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tessellation, 010304 chemical physics, Delaunay triangulation, Proteins, Articles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Visualization, MESH: Internet, protein structures, Laguerre polynomials, protein volume, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Voronoi diagram, computer, Algorithm, Software, MESH: Models, Molecular
Abstract: International audience; Protein structures are an ensemble of atoms determined experimentally mostly by X-ray crystallography or Nuclear Magnetic Resonance. Studying 3D protein structures is a key point for better understanding protein function at a molecular level. We propose a set of accurate tools, for analysing protein structures, based on the reliable method of Voronoi-Laguerre tessellations. The Voronoi Laguerre Delaunay Protein web server (VLDPws) computes the Laguerre tessellation on a whole given system first embedded in solvent. Through this fine description, VLDPws gives the following data: (i) Amino acid volumes evaluated with high precision, as confirmed by good correlations with experimental data. (ii) A novel definition of inter-residue contacts within the given protein. (iii) A measure of the residue exposure to solvent that significantly improves the standard notion of accessibility in some cases. At present, no equivalent web server is available. VLDPws provides output in two complementary forms: direct visualization of the Laguerre tessellation, mostly its polygonal molecular surfaces; files of volumes; and areas, contacts and similar data for each residue and each atom. These files are available for download for further analysis. VLDPws can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/vldp.
Published: 2013

29. PRR repeats in the intracellular domain of KISS1R are important for its export to cell membrane

Author: Chevrier, Lucie, De Brevern, Alexandre, Hernandez, Eva, Leprince, Jérome, Vaudry, Hubert, Guedj, Anne Marie, De Roux, Nicolas, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), INSERM UMR676, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Laboratoire de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, and de Brevern, Alexandre G.
Subjects: DNA Mutational Analysis, Gene Expression, MESH: Receptors, G-Protein-Coupled, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Base Sequence, MESH: Hypogonadism, Receptors, MESH: Obesity, MESH: Animals, MESH: Molecular Dynamics Simulation, MESH: Proline-Rich Protein Domains, MESH: DNA Mutational Analysis, MESH: Genetic Association Studies, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, variants, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: COS Cells, Protein Transport, MESH: HEK293 Cells, Proline-Rich Protein Domains, structural alphabet, MESH: Protein Transport, MESH: Gene Expression, Molecular Sequence Data, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Molecular Dynamics Simulation, G-Protein-Coupled, male, Insertional, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Hypogonadism, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, MESH: Cercopithecus aethiops, MESH: Male, MESH: Mutagenesis, Insertional, Mutagenesis, adolescent, MESH: HeLa Cells, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Cell Membrane
Abstract: The National Institute of Health and Medical Research (INSERM, France) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The Laboratories of Excellence, GR-Ex (France); International audience; Inactivating mutations of KISS-1 receptor (KISS1R) have been recently described as a rare cause of isolated hypogonadotropic hypogonadism transmitted as a recessive trait. Few mutations have been described, and the structure-function relationship of KISS1R remains poorly understood. Here, we have taken advantage of the discovery of a novel mutation of KISS1R to characterize the structure and function of an uncommon protein motif composed of 3 proline-arginine-arginine (PRR) repeats located within the intracellular domain. A heterozygous insertion of 1 PRR repeat in-frame with 3 PRR repeats leading to synthesis of a receptor bearing 4 PRR repeats (PRR-KISS1R) was found in the index case. Functional analysis of PRR-KISS1R showed a decrease of the maximal response to kisspeptin stimulation, associated to a lower cell surface expression without modification of total expression. PRR-KISS1R exerts a dominant negative effect on the synthesis of the wild-type (WT)-KISS1R. This effect was due to the nature of inserted residues but also to the difference of the length of the intracellular domain between PRR-KISS1R and WT-KISS1R. A molecular dynamic analysis showed that the additional PRR constrained this arginine-rich region into a polyproline type II helix. Altogether, this study shows that a heterozygous insertion in KISS1R may lead to hypogonadotropic hypogonadism by a dominant negative effect on the WT receptor. An additional PRR repeat into a proline-arginine-rich motif can dramatically changed the conformation of the intracellular domain of KISS1R and its probable interaction with partner proteins.
Published: 2013

30. Cis-trans isomerization of omega dihedrals in proteins

Author: Pierrick Craveur, Pierre Poulain, Joseph Rebehmed, Agnel Praveen Joseph, Alexandre G. de Brevern, de Brevern, Alexandre G., GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) HFSP (India), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Models, Molecular, cis-trans-Isomerases, Protein Folding, Stereochemistry, Protein Conformation, MESH: Protein Folding, Clinical Biochemistry, Dihedral angle, Molecular Dynamics Simulation, 010402 general chemistry, Crystallography, X-Ray, 01 natural sciences, Biochemistry, iPBA, 03 medical and health sciences, Molecular dynamics, Protein structure, MESH: Protein Conformation, MESH: Protein Stability, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Peptide bond, Humans, MESH: Molecular Dynamics Simulation, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein superimposition, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Humans, Chemistry, Protein Stability, Organic Chemistry, Proteins, Protein structure prediction, protein function, MESH: Crystallography, X-Ray, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cis trans isomerization, 0104 chemical sciences, protein structures, Protein folding, structural alphabet, isomerisation, MESH: cis-trans-Isomerases, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Isomerization, MESH: Models, Molecular
Abstract: International audience; Peptide bonds in protein structures are mainly found in trans conformation with a torsion angle ω close to 180°. Only a very low proportion is observed in cis conformation with ω angle around 0°. Cis-trans isomerization leads to local conformation changes which play an important role in many biological processes. In this paper, we reviewed the recent discoveries and research achievements in this field. First, we presented some interesting cases of biological processes in which cis-trans isomerization is directly implicated. It is involved in protein folding and various aspect of protein function like dimerization interfaces, autoinhibition control, channel gating, membrane binding. Then we reviewed conservation studies of cis peptide bonds which emphasized evolution constraints in term of sequence and local conformation. Finally we made an overview of the numerous molecular dynamics studies and prediction methodologies already developed to take into account this structural feature in the research area of protein modeling. Many cis peptide bonds have not been recognized as such due to the limited resolution of the data and to the refinement protocol used. Cis-trans proline isomerization reactions represents a vast and promising research area that still needs to be further explored for a better understanding of isomerization mechanism and improvement of cis peptide bond predictions.
Published: 2013

31. DoSA: Database of Structural Alignments

Author: Alexandre G. de Brevern, Bernard Offmann, Garima Agarwal, Narayanaswamy Srinivasan, Mohammed Iftekhar, Swapnil Mahajan, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, GR-Ex, Laboratoire d'Excellence, GR-Ex, National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), MBU, Indian Institute of Science-Indian Institute of Science, Indo-French collaborative grant (CEFIPRA/IFCPAR 3903-E) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The University of Nantes (France) Fonds Européen de Dévelopment Régional and Conseil Regional de La Réunion [20100079, Tiers: 144645] Department of Biotechnology (India), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and de Brevern, Alexandre G.
Subjects: Models, Molecular, PALI, substitution matrix, optimisation, Statistics as Topic, MESH: Amino Acid Sequence, Molecular Biophysics Unit, computer.software_genre, Protein structure, MESH: Proteins, Databases, Protein, Structural motif, database, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Structural Homology, Protein, 0303 health sciences, Protein function, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Database, 030302 biochemistry & molecular biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], CLUSTALW, Original Article, Structural alphabet, General Agricultural and Biological Sciences, MESH: Models, Molecular, Information Systems, MESH: Databases, Protein, Molecular Sequence Data, Biology, iPBA, General Biochemistry, Genetics and Molecular Biology, Substitution matrix, Access to Information, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, protein structure, Spatial Orientations, MESH: Statistics as Topic, 030304 developmental biology, MESH: Molecular Sequence Data, Proteins, Protein superfamily, MESH: Access to Information, Functional integrity, Structural Homology, Protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], protein structure superimposition, computer
Abstract: International audience; Protein structure alignment is a crucial step in protein structure-function analysis. Despite the advances in protein structure alignment algorithms, some of the local conformationally similar regions are mislabeled as structurally variable regions (SVRs). These regions are not well superimposed because of differences in their spatial orientations. The Database of Structural Alignments (DoSA) addresses this gap in identification of local structural similarities obscured in global protein structural alignments by realigning SVRs using an algorithm based on protein blocks. A set of protein blocks is a structural alphabet that abstracts protein structures into 16 unique local structural motifs. DoSA provides unique information about 159,780 conformationally similar and 56,140 conformationally dissimilar SVRs in 74 705 pairwise structural alignments of homologous proteins. The information provided on conformationally similar and dissimilar SVRs can be helpful to model loop regions. It is also conceivable that conformationally similar SVRs with conserved residues could potentially contribute toward functional integrity of homologues, and hence identifying such SVRs could be helpful in understanding the structural basis of protein function. Database URL: http://bo-protscience.fr/dosa/
Published: 2013

32. Progressive structure-based alignment of homologous proteins: Adopting sequence comparison strategies

Author: Joseph, Agnel Praveen, Srinivasan, Narayanaswamy, De Brevern, Alexandre, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, French Ministry of Research, University of Paris Diderot - Paris 7, Sorbone Paris Cité, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM), Indian Department of Biotechnology, CEFIPRA/IFCPAR for collaborative grant (number 3903-E)., and de Brevern, Alexandre G.
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Sequence Homology, Amino Acid, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Sequence Alignment, structure conservation, protein structure mining, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Protein Conformation, Protein Data Bank, Protein Blocks, anchor-based alignment, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure comparison, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Models, Molecular, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; Comparison of multiple protein structures has a broad range of applications in the analysis of protein structure, function and evolution. Multiple structure alignment tools (MSTAs) are necessary to obtain a simultaneous comparison of a family of related folds. In this study, we have developed a method for multiple structure comparison largely based on sequence alignment techniques. A widely used Structural Alphabet named Protein Blocks (PBs) was used to transform the information on 3D protein backbone conformation as a 1D sequence string. A progressive alignment strategy similar to CLUSTALW was adopted for multiple PB sequence alignment (mulPBA). Highly similar stretches identified by the pairwise alignments are given higher weights during the alignment. The residue equivalences from PB based alignments are used to obtain a three dimensional fit of the structures followed by an iterative refinement of the structural superposition. Systematic comparisons using benchmark datasets of MSTAs underlines that the alignment quality is better than MULTIPROT, MUSTANG and the alignments in HOMSTRAD, in more than 85% of the cases. Comparison with other rigid-body and flexible MSTAs also indicate that mulPBA alignments are superior to most of the rigid-body MSTAs and highly comparable to the flexible alignment methods.
Published: 2012

33. PredyFlexy: flexibility and local structure prediction from sequence

Author: Catherine Etchebest, Alexandre G. de Brevern, Pierrick Craveur, Aurélie Bornot, Jean-Christophe Gelly, de Brevern, Alexandre G., Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Ministry of Research (France) University Paris Diderot, Sorbonne Paris Cité, National Institute for Blood Transfusion (INTS, France) Institute for Health and Medical Research (INSERM, France)
Subjects: Protein Conformation, MESH: Sequence Analysis, Protein, Protein Data Bank, Bioinformatics, computer.software_genre, Crystallography, X-Ray, Root mean square, Protein structure, Software, MESH: Protein Conformation, Sequence Analysis, Protein, MESH: Molecular Dynamics Simulation, protein folds, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, Sequence, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030302 biochemistry & molecular biology, Articles, disorder, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Internet, structural alphabet, Algorithm, amino acid, Web server, MESH: Motion, Biology, Molecular Dynamics Simulation, Long Structural Prototypes, Set (abstract data type), 03 medical and health sciences, Motion, MESH: Software, Support Vector Machines, evolutionary information, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Flexibility (engineering), Internet, business.industry, MESH: Crystallography, X-Ray, Key (cryptography), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer
Abstract: International audience; Protein structures are necessary for understanding protein function at a molecular level. Dynamics and flexibility of protein structures are also key elements of protein function. So, we have proposed to look at protein flexibility using novel methods: (i) using a structural alphabet and (ii) combining classical X-ray B-factor data and molecular dynamics simulations. First, we established a library composed of structural prototypes (LSPs) to describe protein structure by a limited set of recurring local structures. We developed a prediction method that proposes structural candidates in terms of LSPs and predict protein flexibility along a given sequence. Second, we examine flexibility according to two different descriptors: X-ray B-factors considered as good indicators of flexibility and the root mean square fluctuations, based on molecular dynamics simulations. We then define three flexibility classes and propose a method based on the LSP prediction method for predicting flexibility along the sequence. This method does not resort to sophisticate learning of flexibility but predicts flexibility from average flexibility of predicted local structures. The method is implemented in PredyFlexy web server. Results are similar to those obtained with the most recent, cutting-edge methods based on direct learning of flexibility data conducted with sophisticated algorithms. PredyFlexy can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/predyflexy/.
Published: 2012

34. Selective constraint on human pre-mRNA splicing by protein structural properties

Author: Trees-Juen Chuang, Alexandre G. de Brevern, Feng-Chi Chen, Hsuan-Yu Lin, Jean-Christophe Gelly, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Population Health Sciences [Taiwan], National Health Research Institutes [Taiwan] (NHRI), Genomics Research Center, Academia Sinica, Department of Biological Science and Technology [Hsinchu], National Chiao Tung University (NCTU), Department of Dentistry, China Medical University, National Health Research Institutes, Taiwan, National Science Council, Taiwan. (NSC 101-2311-B-400-003 to FCC, NSC 99-2911-I-001-017 (Programme of Integrated Actions ORCHID) and NSC99-2628-B-001-008-MY3 to TJC), Ministry of Research, France, University of Paris Diderot, Sorbonne Paris Cité, France, National Institute for Blood Transfusion (INTS), France, Institute for Health and Medical Research (INSERM), France, Partenariat Hubert Curien (PHC) Orchid for French - Taiwanese collaboration, 'Investissements d'avenir', Laboratories of Excellence GR-Ex., and de Brevern, Alexandre G.
Subjects: Proteomics, MESH: Protein Structure, Quaternary, MESH: Selection, Genetic, [SDV.GEN] Life Sciences [q-bio]/Genetics, Exon, Negative selection, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Protein structure, Gene Frequency, RNA Precursors, Research Articles, MESH: Evolution, Molecular, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Alternative Splicing, MESH: Proteomics, protein domain, Exons, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], RNA splicing, protein unit, protein structural constraint, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Protein domain, MESH: RNA Precursors, Biology, diseases, Evolution, Molecular, 03 medical and health sciences, alternative splicing, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, genomics, MESH: Gene Frequency, Humans, human, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Selection, Genetic, Protein Structure, Quaternary, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, MESH: RNA, Messenger, Messenger RNA, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Alternative splicing, RNA, Protein Structure, Tertiary, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Exons, 030217 neurology & neurosurgery
Abstract: International audience; Alternative splicing (AS) is a major mechanism of increasing proteome diversity in complex organisms. Different AS transcript isoforms may be translated into peptide sequences of significantly different lengths and amino acid compositions. One important question, then, is how AS is constrained by protein structural requirements while peptide sequences may be significantly changed in AS events. Here, we address this issue by examining whether the intactness of three-dimensional protein structural units (compact units in protein structures, namely protein units [PUs]) tends to be preserved in AS events in human. We show that PUs tend to occur in constitutively spliced exons and to overlap constitutive exon boundaries. Furthermore, when PUs are located at the boundaries between two alternatively spliced exons (ASEs), these neighboring ASEs tend to co-occur in different transcript isoforms. In addition, such PU-spanned ASE pairs tend to have a higher frequency of being included in transcript isoforms. ASE regions that overlap with PUs also have lower nonsynonymous-to-synonymous substitution rate ratios than those that do not overlap with PUs, indicating stronger negative selection pressure in PU-overlapped ASE regions. Of note, we show that PUs have protein domain- and structural orderness-independent effects on messenger RNA (mRNA) splicing. Overall, our results suggest that fine-scale protein structural requirements have significant influences on the splicing patterns of human mRNAs.
Published: 2012

35. Local structural differences in homologous proteins: specificities in different SCOP classes

Author: Joseph, Agnel Praveen, Valadié, Hélène, Srinivasan, Narayanaswamy, De Brevern, Alexandre, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Molecular Biophysics Unit, Indian Institute of Science, French Ministry of Research, University of Paris Diderot - Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM), Indian Department of Biotechnology, CEFIPRA/IFCPAR for collaborative grant (number 3903-E)., and de Brevern, Alexandre G.
Subjects: structure comparison, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], local structures, backbone conformation, MESH: Protein Structure, Secondary, Protein Data Bank, MESH: Amino Acid Sequence, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], indel, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], amino acid, protein folds, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; The constant increase in the number of solved protein structures is of great help in understanding the basic principles behind protein folding and evolution. 3-D structural knowledge is valuable in designing and developing methods for comparison, modelling and prediction of protein structures. These approaches for structure analysis can be directly implicated in studying protein function and for drug design. The backbone of a protein structure favours certain local conformations which include α-helices, β-strands and turns. Libraries of limited number of local conformations (Structural Alphabets) were developed in the past to obtain a useful categorization of backbone conformation. Protein Block (PB) is one such Structural Alphabet that gave a reasonable structure approximation of 0.42 Å. In this study, we use PB description of local structures to analyse conformations that are preferred sites for structural variations and insertions, among group of related folds. This knowledge can be utilized in improving tools for structure comparison that work by analysing local structure similarities. Conformational differences between homologous proteins are known to occur often in the regions comprising turns and loops. Interestingly, these differences are found to have specific preferences depending upon the structural classes of proteins. Such class-specific preferences are mainly seen in the all-β class with changes involving short helical conformations and hairpin turns. A test carried out on a benchmark dataset also indicates that the use of knowledge on the class specific variations can improve the performance of a PB based structure comparison approach. The preference for the indel sites also seem to be confined to a few backbone conformations involving β-turns and helix C-caps. These are mainly associated with short loops joining the regular secondary structures that mediate a reversal in the chain direction. Rare β-turns of type I' and II' are also identified as preferred sites for insertions.
Published: 2012

36. Improvement of protein structure comparison using a structural alphabet

Author: Alexandre G. de Brevern, Agnel Praveen Joseph, Narayanaswamy Srinivasan, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, These works were supported by grants from the French Ministry of Research, University of Paris Diderot - Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM) and Department of Biotechnology, India., and de Brevern, Alexandre G.
Subjects: Models, Molecular, MESH: Databases, Protein, Protein Folding, Structural similarity, Protein Conformation, MESH: Protein Folding, Structural alignment, MESH: Sequence Alignment, Sequence alignment, MESH: Algorithms, Biology, Biochemistry, Substitution matrix, 03 medical and health sciences, Protein structure, MESH: Protein Conformation, Protein Data Bank, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Databases, Protein, protein folds, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, Multiple sequence alignment, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], semi-global alignment, 030302 biochemistry & molecular biology, Proteins, structural comparison, protein structure mining, General Medicine, computer.file_format, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Crystallography, Protein Blocks, Protein folding, structural alphabet, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biological system, computer, Sequence Alignment, Algorithms, amino acid, anchorbased alignment, MESH: Models, Molecular
Abstract: International audience; The three dimensional structure of a protein provides major insights into its function. Protein structure comparison has implications in functional and evolutionary studies. A structural alphabet (SA) is a library of local protein structure prototypes that can abstract every part of protein main chain conformation. Protein Blocks (PBs) is a widely used SA, composed of 16 prototypes, each representing a pentapeptide backbone conformation defined in terms of dihedral angles. Through this description, the 3D structural information can be translated into a 1D sequence of PBs. In a previous study, we have used this approach to compare protein structures encoded in terms of PBs. A classical sequence alignment procedure based on dynamic programming was used, with a dedicated PB Substitution Matrix (SM). PB-based pairwise structural alignment method gave an excellent performance, when compared to other established methods for mining. In this study, we have (i) refined the SMs and (ii) improved the Protein Block Alignment methodology (named as iPBA). The SM was normalized in regards to sequence and structural similarity. Alignment of protein structures often involves similar structural regions separated by dissimilar stretches. A dynamic programming algorithm that weighs these local similar stretches has been designed. Amino acid substitutions scores were also coupled linearly with the PB substitutions. iPBA improves (i) the mining efficiency rate by 6.8% and (ii) more than 82% of the alignments have a better quality. A higher efficiency in aligning multi-domain proteins could be also demonstrated. The quality of alignment is better than DALI and MUSTANG in 81.3% of the cases. Thus our study has resulted in an impressive improvement in the quality of protein structural alignment.
Published: 2011

37. iPBA: a tool for protein structure comparison using sequence alignment strategies.: Structural Alphabet Alignment

Author: Gelly, Jean-Christophe, Joseph, Agnel Praveen, Srinivasan, Narayanaswamy, de Brevern, Alexandre, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, CEFIPRA number 3903 French Ministry of Research University of Paris Diderot - Paris 7 French National Institute for Blood Transfusion (INTS) French Institute for Health and Medical Research (INSERM) Department of Biotechnology, India, and de Brevern, Alexandre G.
Subjects: MESH: Databases, Protein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], semi-global alignment, MESH: Sequence Analysis, Protein, MESH: Sequence Alignment, structural comparison, protein structure mining, MESH: Algorithms, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Software, MESH: Protein Conformation, Protein Data Bank, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], amino acid, anchorbased alignment, protein folds, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; With the immense growth in the number of available protein structures, fast and accurate structure comparison has been essential. We propose an efficient method for structure comparison, based on a structural alphabet. Protein Blocks (PBs) is a widely used structural alphabet with 16 pentapeptide conformations that can fairly approximate a complete protein chain. Thus a 3D structure can be translated into a 1D sequence of PBs. With a simple Needleman-Wunsch approach and a raw PB substitution matrix, PB-based structural alignments were better than many popular methods. iPBA web server presents an improved alignment approach using (i) specialized PB Substitution Matrices (SM) and (ii) anchor-based alignment methodology. With these developments, the quality of ∼88% of alignments was improved. iPBA alignments were also better than DALI, MUSTANG and GANGSTA(+) in >80% of the cases. The webserver is designed to for both pairwise comparisons and database searches. Outputs are given as sequence alignment and superposed 3D structures displayed using PyMol and Jmol. A local alignment option for detecting subs-structural similarity is also embedded. As a fast and efficient 'sequence-based' structure comparison tool, we believe that it will be quite useful to the scientific community. iPBA can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/ipba/.
Published: 2011

38. Comparative analysis of threshold and tessellation methods for determining protein contacts

Author: Esque, Jeremy, Oguey, Christophe, de Brevern, Alexandre, Laboratoire de Physique Théorique et Modélisation (LPTM - UMR 8089), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), French Ministry of Research, Paris Diderot University Paris 7, French National Center for Scientific Research (CNRS), French National Institute for Blood Transfusion (INTS), French National Institute for Health and Medical Research (INSERM), French Ministry of Higher Education and Research., and de Brevern, Alexandre G.
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Delaunay diagram, Laguerre tessellation, MESH: Protein Folding, MESH: Hydrophobic and Hydrophilic Interactions, residue accessibility, MESH: Protein Structure, Secondary, secondary structure, protein contacts, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Protein Stability, [MATH.MATH-GT]Mathematics [math]/Geometric Topology [math.GT], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Binding, MESH: Disulfides, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Voronoi tessellation, MESH: Models, Molecular, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], [MATH.MATH-GT] Mathematics [math]/Geometric Topology [math.GT]
Abstract: International audience; The 3D structure of a protein is the main physical support of a protein's biological function; 3D protein folds are primarily maintained through interactions between amino acids. Inter-residue contacts are essential for the stability of protein folds. Therefore, many methodologies in the fields of structure analysis, structure prediction, and structure-function relationships are based on residue contacts. The present study provides a comparative analysis of two approaches for determining contacts: the classical distance-threshold method and an application of Laguerre, or weighted Voronoi tessellation. First, we examined mean contact distributions and their dependence on residue volumes, accessibility and hydrophobicity. In general, the different methods gave concordant results, although the method based on Cα distances showed significant discrepancies with the all-atom tessellation method. We also analyzed preferential contacts between all amino acid species and studied the influence of protein chain length, the proximity of the residues along the sequence, and the secondary structure environment. Interestingly, the discrepancies between methods were occasionally large enough to substantially change the relative preferences of some contacts. Finally, a case study on disulfide bridges demonstrated the importance of the structural environment in determining contacts from tessellation. In conclusion, the tessellation method is more accurate because of its fine adaptation to local protein topology, with far-reaching implications for most contact-based prediction methods of protein folding.
Published: 2011

39. Species specific amino acid sequence-protein local structure relationships: An analysis in the light of a structural alphabet

Author: de Brevern, Alexandre, Joseph, Agnel Praveen, de Brevern, Alexandre G., Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and French Ministry of Research University Paris Diderot the Institute of Blood Transfusion (INTS) the Institute for Health and Medical Research(INSERM).
Subjects: MESH: Databases, Protein, amino acids, MESH: Amino Acids, MESH: Molecular Sequence Data, malaria, MESH: Protein Structure, Secondary, secondary structure, MESH: Amino Acid Sequence, MESH: Saccharomyces cerevisiae, MESH: Cluster Analysis, MESH: Proteome, MESH: Structure-Activity Relationship, Protein Blocks, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Species Specificity, structural alphabet, MESH: Arabidopsis, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein folds, MESH: Plasmodium falciparum
Abstract: International audience; Protein structure analysis and prediction methods are based on non-redundant data extracted from the available protein structures, regardless of the species from which the protein originates. Hence, these datasets represent the global knowledge on protein folds, which constitutes a generic distribution of amino acid sequence-protein structure (AAS-PS) relationships. In this study, we try to elucidate whether the AAS-PS relationship could possess specificities depending on the specie. For this purpose, we have chosen three different species: Saccharomyces cerevisiae, Plasmodium falciparum and Arabidopsis thaliana. We analyzed the AAS-PS behaviors of the proteins from these three species and compared it to the "expected" distribution of a classical non-redundant databank. With the classical secondary structure description, only slight differences in amino acid preferences could be observed. With a more precise description of local protein structures (Protein Blocks), significant changes could be highlighted. S. cerevisiae's AAS-PS relationship is close to the general distribution, while striking differences are observed in the case of A. thaliana. P. falciparum is the most distant one. This study presents some interesting view-points on AAS-PS relationship. Certain species exhibit unique preferences for amino acids to be associated with protein local structural elements. Thus, AAS-PS relationships are species dependent. These results can give useful insights for improving prediction methodologies which take the species specific information into account.
Published: 2011

40. Assignment of PolyProline II Conformation and Analysis of Sequence - Structure Relationship

Author: Alexandre G. de Brevern, Jean-Christophe Gelly, Agnel Praveen Joseph, Yohann Mansiaux, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), Ministère de la Recherche, Université Paris Diderot - Paris 7, National Institute for Blood Transfusion (INTS) National Institute for Health and Medical Research (INSERM), CEFIPRA grant (number 3903-E)., and de Brevern, Alexandre G.
Subjects: Macromolecular Assemblies, Protein Folding, MESH: secondary structure assignment method, MESH: structural alphabet, lcsh:Medicine, Molecular Dynamics, Biochemistry, Protein Structure, Secondary, Molecular dynamics, Protein structure, Computational Chemistry, [STAT.AP] Statistics [stat]/Applications [stat.AP], Macromolecular Structure Analysis, lcsh:Science, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Chemistry, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Classes, MESH: secondary structure, MESH: Protein Blocks, Sequence structure, Research Article, Protein Structure, 030303 biophysics, Biophysics, Computational biology, Dihedral angle, Protein–protein interaction, 03 medical and health sciences, Structure-Activity Relationship, MESH: turns, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: coil, Biology, Theoretical Biology, MESH: PolyProline, 030304 developmental biology, Polyproline helix, lcsh:R, Proteins, Computational Biology, MESH: DSSP, Structural biology, Helix, MESH: sequence structure relationship, lcsh:Q, Structural Genomics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Peptides
Abstract: International audience; BACKGROUND: Secondary structures are elements of great importance in structural biology, biochemistry and bioinformatics. They are broadly composed of two repetitive structures namely α-helices and β-sheets, apart from turns, and the rest is associated to coil. These repetitive secondary structures have specific and conserved biophysical and geometric properties. PolyProline II (PPII) helix is yet another interesting repetitive structure which is less frequent and not usually associated with stabilizing interactions. Recent studies have shown that PPII frequency is higher than expected, and they could have an important role in protein - protein interactions. METHODOLOGY/PRINCIPAL FINDINGS: A major factor that limits the study of PPII is that its assignment cannot be carried out with the most commonly used secondary structure assignment methods (SSAMs). The purpose of this work is to propose a PPII assignment methodology that can be defined in the frame of DSSP secondary structure assignment. Considering the ambiguity in PPII assignments by different methods, a consensus assignment strategy was utilized. To define the most consensual rule of PPII assignment, three SSAMs that can assign PPII, were compared and analyzed. The assignment rule was defined to have a maximum coverage of all assignments made by these SSAMs. Not many constraints were added to the assignment and only PPII helices of at least 2 residues length are defined. CONCLUSIONS/SIGNIFICANCE: The simple rules designed in this study for characterizing PPII conformation, lead to the assignment of 5% of all amino as PPII. Sequence - structure relationships associated with PPII, defined by the different SSAMs, underline few striking differences. A specific study of amino acid preferences in their N and C-cap regions was carried out as their solvent accessibility and contact patterns. Thus the assignment of PPII can be coupled with DSSP and thus opens a simple way for further analysis in this field.
Published: 2011

41. A bioinformatic web server to cut protein structures in terms of Protein Units

Author: Gelly, Jean-Christophe, de Brevern, Alexandre, de Brevern, Alexandre G., Jaclyn E. Morris, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by grants from the Ministère de la Recherche, Université Paris Diderot - Paris 7, National Institute for Blood Transfusion (INTS) and the National Institute for Health and Medical Research (INSERM).
Subjects: protein interactions, algorithm, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], protein flexibility, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], protein functions, webserver, protein folding, protein structures, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: Analysis of the architecture and organization of protein structures is a major challenge to better understand protein flexibility, folding, functions and interactions with their partners and to design new drugs. Protein structures are often described as series of alpha-helices and beta-sheets, or at a higher level as an arrangement of protein domains. Due to the lack of an intermediate vision which could give a good understanding and description of protein structure architecture, we have proposed a novel intermediate view, the Protein Units (PUs). They are novel level of protein structure description between secondary structures and domains. A PU is defined as a compact sub-region of the 3D structure corresponding to one sequence fragment, defined by a high number of intra-PU contacts and a low number of inter-PU contacts. The methodology to obtain PUs from the protein structures is named Protein Peeling (PP). For the algorithm, the protein structures are described as a succession of Ca. The distances between Ca are translated into contact probabilities using a logistic function. Protein Peeling only uses this contact probability matrix. An optimization procedure, based on the Matthews' coefficient correlation (MCC) between contacts probability sub matrices, defines optimal cutting points that separate the region examined into two or three PUs. The process is iterated until the compactness of the resulting PUs reaches a given limit. An index assesses the compactness quality and relative independence of each PU. Protein Peeling is a tool to better understand and analyze the organization of protein structures. We have developed a dedicated bioinformatic web server: Protein Peeling 2 (PP2). Given the 3D coordinates of a protein, it proposes an automatic identification of protein units (PUs). The interface component consists of a web page (HTML) and common gateway interface (CGI). The user can set many parameters and upload a given structure in PDB file format to a perl core instance. This last component is a module that embeds all the information necessary for two others softwares (mainly coded in C to perform most of the computation tasks and R for the analysis). Results are given both textually and graphically using JMol applet and PyMol software. The server can be accessed from http://www.dsimb.inserm.fr/dsimb_tools/peeling/. Only one equivalent on line methodology is available.
Published: 2011

42. Le cahier de laboratoire électronique (CLE)

Author: Amiard, Anabelle, Baczynski, Céline, Blanchet, Christophe, de Brevern, Alexandre, Dorlanne-Messiaen, Emmanuelle, Grognard, Eric, Kisselova, Galina, Malpertuy, Alain, Menez Jamet, Jeanne, Racle, Ivan, Rouger, Céline, de Brevern, Alexandre G., Sanofi, Fovea Pharmaceuticals/Vision Institute, SANOFI Recherche, Novo Nordisk Production SAS, Novo Nordisk, Agilent Technologies France, DSIMB, U 665, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), ProductLife (ProductLife), ProductLife, Cambridgesoft, Ipsen, IPSEN, Atragene Informatics, Vaxon Biotech, I. Racle, Bayer Santé familiale SAS, Bayer HealthCare SAS, and Laboratoires Expanscience
Subjects: [SPI.OTHER]Engineering Sciences [physics]/Other, Information sharing, Intellectual property, Electronic signature, Archives, [SPI.OTHER] Engineering Sciences [physics]/Other, GLP, [INFO.INFO-SE] Computer Science [cs]/Software Engineering [cs.SE], [INFO.INFO-SE]Computer Science [cs]/Software Engineering [cs.SE], Regulatory, Electronic laboratory notebook (eLN), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, LIMS, Patent, Legal, Law, 21CFR Part 11
Abstract: International audience; The laboratory notebook is an essential tool in the company and in the laboratory. It allows durable follow-up of experiments; it is also an essential legal tool. Its electronic versions have become increasingly efficient over recent years, providing new functions, more rapid access to data and aid to decision-making, but they also raise new questions concerning their ease of use and their possible limitations. This article is designed to summarize the specificities and advantages of the electronic laboratory notebook as well as its current limitations.
Published: 2011

43. Identification of local conformational similarity in structurally variable regions of homologous proteins using protein blocks

Author: Garima Agarwal, Narayanaswamy Srinivasan, Swapnil Mahajan, Alexandre G. de Brevern, Molecular Biophysics Unit, Indian Institute of Science, National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), Institut National de la Transfusion Sanguine [Paris] (INTS), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Council of Scientific and Industrial Research Department of Biotechnology CEFIPRA collaborative grant (number 3903-E) Université Paris Diderot - Paris 7 National l Institute for Blood Transfusion (INTS) National Institute for Health and Medical Research (INSERM), and de Brevern, Alexandre G.
Subjects: Models, Molecular, Protein Folding, Structural comparison, Protein Conformation, Structural alphabet, lcsh:Medicine, Molecular Biophysics Unit, Bioinformatics, Biochemistry, Protein structure, Macromolecular Structure Analysis, lcsh:Science, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Physics, 0303 health sciences, Multidisciplinary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030302 biochemistry & molecular biology, Rigid body, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein blocks, Sequence Analysis, Research Article, Protein Structure, Biophysics, Biological Data Management, Sequence alignment, Computational biology, Structural alignment, 03 medical and health sciences, Molecular evolution, Secondary structure, Evolutionary Modeling, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Evolutionary Systematics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology, Theoretical Biology, Structure comparison, Protein folds, 030304 developmental biology, Evolutionary Biology, lcsh:R, Proteins, Computational Biology, Protein superfamily, lcsh:Q, Threading (protein sequence), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Topological conjugacy
Abstract: International audience; Structure comparison tools can be used to align related protein structures to identify structurally conserved and variable regions and to infer functional and evolutionary relationships. While the conserved regions often superimpose well, the variable regions appear non superimposable. Differences in homologous protein structures are thought to be due to evolutionary plasticity to accommodate diverged sequences during evolution. One of the kinds of differences between 3-D structures of homologous proteins is rigid body displacement. A glaring example is not well superimposed equivalent regions of homologous proteins corresponding to α-helical conformation with different spatial orientations. In a rigid body superimposition, these regions would appear variable although they may contain local similarity. Also, due to high spatial deviation in the variable region, one-to-one correspondence at the residue level cannot be determined accurately. Another kind of difference is conformational variability and the most common example is topologically equivalent loops of two homologues but with different conformations. In the current study, we present a refined view of the "structurally variable" regions which may contain local similarity obscured in global alignment of homologous protein structures. As structural alphabet is able to describe local structures of proteins precisely through Protein Blocks approach, conformational similarity has been identified in a substantial number of 'variable' regions in a large data set of protein structural alignments; optimal residue-residue equivalences could be achieved on the basis of Protein Blocks which led to improved local alignments. Also, through an example, we have demonstrated how the additional information on local backbone structures through protein blocks can aid in comparative modeling of a loop region. In addition, understanding on sequence-structure relationships can be enhanced through our approach. This has been illustrated through examples where the equivalent regions in homologous protein structures share sequence similarity to varied extent but do not preserve local structure.
Published: 2011

44. Predicting protein flexibility through the prediction of local structures

Author: Alexandre G. de Brevern, Catherine Etchebest, Aurélie Bornot, de Brevern, Alexandre G., Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), and National Institute for Blood Transfusion (INTS), the French Institute for Health and Medical Research (INSERM), University of Paris Diderot - Paris 7, French Ministry of Research.
Subjects: Protein structure database, Protein Conformation, Computer science, Bioinformatics, flexibility prediction, Context (language use), Molecular Dynamics Simulation, Machine learning, computer.software_genre, Biochemistry, Article, Set (abstract data type), 03 medical and health sciences, Protein structure, X-Ray Diffraction, Structural Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Flexibility (engineering), 0303 health sciences, Sequence, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Basis (linear algebra), business.industry, 030302 biochemistry & molecular biology, Proteins, Protein structure prediction, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], protein structure prediction, protein dynamics, structural alphabet, Data mining, Artificial intelligence, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer
Abstract: International audience; Protein structures are valuable tools for understanding protein function. However, protein dynamics is also considered a key element in protein function. Therefore, in addition to structural analysis, fully understanding protein function at the molecular level now requires accounting for flexibility. However, experimental techniques that produce both types of information simultaneously are still limited. Prediction approaches are useful alternative tools for obtaining otherwise unavailable data. It has been shown that protein structure can be described by a limited set of recurring local structures. In this context, we previously established a library composed of 120 overlapping long structural prototypes (LSPs) representing fragments of 11 residues in length and covering all known local protein structures. On the basis of the close sequence-structure relationship observed in LSPs, we developed a novel prediction method that proposes structural candidates in terms of LSPs along a given sequence. The prediction accuracy rate was high given the number of structural classes. In this study, we use this methodology to predict protein flexibility. We first examine flexibility according to two different descriptors, the B-factor and root mean square fluctuations from molecular dynamics simulations. We then show the relevance of using both descriptors together. We define three flexibility classes and propose a method based on the LSP prediction method for predicting flexibility along the sequence. The prediction rate reaches 49.6%. This method competes rather efficiently with the most recent, cutting-edge methods based on true flexibility data learning with sophisticated algorithms. Accordingly, flexibility information should be taken into account in structural prediction assessments. Proteins 2011. © 2010 Wiley-Liss, Inc.
Published: 2011

45. Characterization of Conformational Patterns in Active and Inactive Forms of Kinases Using Protein Blocks Approach

Author: Dhurvas Chandrasekaran Dinesh, Alexandre G. de Brevern, Narayanaswamy Srinivasan, Garima Agarwal, Molecular Biophysics Unit, Indian Institute of Science, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ujjwal Maulik, Sanghamitra Bandyopadhyay, Jason T. L. Wang, de Brevern, Alexandre G., and Ujjwal Maulik, Sanghamitra Bandyopadhyay, Jason T. L. Wang
Subjects: protein interactions, 030303 biophysics, Computational biology, Dihedral angle, Biology, Pentapeptide repeat, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Representation (mathematics), [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, 0303 health sciences, Sequence, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], String (computer science), protein kinase, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein tertiary structure, Crystallography, Protein Blocks, Unsupervised learning, structural alphabet, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], protein, protein structure superimposition, Function (biology)
Abstract: The three-dimensional structure being critical for the function of a protein is usually conserved during evolution. It holds a wealth of information which can be harnessed to understand various aspects of proteins including sequence- structure function and evolutionary relationships. The understanding of these complex relationships is facilitated by a simplistic one-dimensional representation of the tertiary structure like a string of letters. The advantage is an easier visualization without losing much of the vital information due to dimension reduction. Using various methodologies, local structural patterns that can be combined to generate the desired backbone conformation, have been identified that use atomic coordinates characterising three-dimensional structures of proteins. Protein Blocks (PBs) is a set of 16 such local structural descriptors, denoted by letters a .. p that has been derived using unsupervised machine learning algorithms and can approximate the three dimensional space of proteins. Each letter corresponds to a entapeptide with distinct values of 8 dihedral angles (phi, psi). We demonstrate the use of PBs to characterize structural variations in enzymes using kinases as the case study. A protein kinase undergoes structural alterations as it switches to its active conformation from its inactive form. Crystal structures of several protein kinases are available in different enzymatic states. Firstly, we have applied PBs approach in distinguishing between conformation changes and rigid body displacements between the structures of active and inactive forms of a kinase. Secondly, we have performed a comparison of conformational patterns of active forms of a kinase with the active and inactive forms of a closely related kinase. Thirdly, we have studied the structural differences in the active states of homologous kinases. Such studies might help in understanding the structural differences among these enzymes at a different level as well as guide in making drug targets for a specific kinase. The first section gives a brief introduction on PBs and protein kinases followed by the analyses on conformational plasticity in kinases using Protein Blocks.
Published: 2010

46. A short survey on protein blocks

Author: Bernard Offmann, Lakshmipuram S. Swapna, Garima Agarwal, Jean-Christophe Gelly, Narayanaswamy Srinivasan, Alexandre G. de Brevern, Bohdan Schneider, Catherine Etchebest, Swapnil Mahajan, Manoj Tyagi, Frédéric Cadet, Aurélie Bornot, Hélène Valadié, Agnel Praveen Joseph, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Computational Biology Branch, NLM-NCBI, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Biotechnology AS CR, These works were supported by grants from the French Ministry of Research, University of Paris Diderot - Paris 7, University of Saint-Denis de la Réunion, French National Institute for Blood Transfusion (INTS), French National Institute for Health and Medical Research (INSERM) and Indian Department of Biotechnology. APJ and GA are supported by CEFIPRA number 3903-E and Council of Scientific and Industrial Research, respectively. AB had a grant from the French Ministry of Research, MT has a post-doctoral fellowship from NIH and HV had a post-doctoral fellowship from CEA. NS and AdB acknowledge to CEFIPRA for collaborative grant (number 3903-E). BS and AdB acknowledge to Partenariat Hubert Curien Barrande (2010-2011)., National Centre for Biological Sciences (NCBS), Tata Institute of Fundamental Research [Bombay] (TIFR), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and de Brevern, Alexandre G.
Subjects: Bayes theorem, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Computer science, Biophysics, Review, computer.software_genre, 03 medical and health sciences, Development (topology), Protein structure, Structural Biology, Support Vector Machines, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cluster (physics), biochemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, 0303 health sciences, Sequence, Quantitative Biology::Biomolecules, amino acids, secondary structures, structural superimposition, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], propensities, binding site, 030302 biochemistry & molecular biology, State (functional analysis), Atomic coordinates, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], structure prediction, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Support vector machine, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, protein structures, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Structural alphabet, structural alphabet, Data mining, mutation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Algorithm, computer
Abstract: Protein structures are classically described in terms of secondary structures. However, even if the regular secondary structures have relevant physical meaning, their recognition based on atomic coordinates has a number of important limitations, such as uncertainties in the assignment of the boundaries of the helical and β-strand regions. In addition, an average of about 50% of all residues are assigned to an irregular state, i.e., the coil. These limitations have led different research teams to focus on abstracting the conformation of the protein backbone in the localized short stretches. To this end, different geometric measures are being used to cluster local stretches in protein structures in a chosen number of states. A prototype representative of the local structures in each cluster is then generally defined. These libraries of local structure prototypes are named "structural alphabets". We have developed a structural alphabet, denoted protein blocks, not only to approximate the protein structure but also to predict them from the sequence. Since its development, we and others have explored numerous new research fields using this structural alphabet. Here, we review some of the most interesting applications of this structural alphabet.
Published: 2010

47. Multiple interests in structural models of DARC transmembrane protein

Author: Yves Colin, Catherine Etchebest, Dorota Smolarek, A.G. de Brevern, Olivier F. Bertrand, Marcin Czerwinski, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Ministry of Research, Université Paris Diderot - Paris 7, French National Institute for Blood Transfusion (INTS), French Institute for Health and Medical Research (INSERM), grant no. N N302 118835 from the Ministry of Science and Higher Education of Poland, Polonium Partenariat Hubert Curien grant., and de Brevern, Alexandre G.
Subjects: MESH: Chemotaxis, Models, Molecular, Chemokine, MESH: Sequence Homology, Amino Acid, Clinical Biochemistry, Plasmodium vivax, MESH: Amino Acid Sequence, Chemokine receptor, 0302 clinical medicine, cancer, MESH: Animals, MESH: Receptors, Cell Surface, 0303 health sciences, biology, Chemotaxis, bioinformatics, Hematology, MESH: Chemokines, Ligand (biochemistry), Transmembrane protein, MESH: Plasmodium vivax, 3. Good health, 030220 oncology & carcinogenesis, MESH: Receptor, Adenosine A2A, flexible docking, camelid VHHs, Chemokines, MESH: Models, Molecular, MESH: Mutation, Receptor, Adenosine A2A, Molecular Sequence Data, malaria, Receptors, Cell Surface, Computational biology, 03 medical and health sciences, MESH: Computer Simulation, transmembrane protein, Consensus Sequence, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Consensus sequence, Malaria, Vivax, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Computer Simulation, MESH: Consensus Sequence, Interleukin 8, Amino Acid Sequence, comparative modelling, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Sequence Homology, Amino Acid, Biochemistry (medical), MESH: Malaria, Vivax, biology.organism_classification, protein docking, MESH: Duffy Blood-Group System, Immunology, Mutation, biology.protein, Duffy Blood-Group System
Abstract: International audience; Duffy Antigen Receptor for Chemokines (DARC) is an unusual transmembrane chemokine receptor which (i) binds the two main chemokine families and (ii) does not transduct any signal as it lacks the DRY consensus sequence. It is considered as silent chemokine receptor, a tank useful for chemiotactism. DARC had been particularly studied as a major actor of malaria infection by Plasmodium vivax. It is also implicated in multiple chemokine inflammation, inflammatory diseases, in cancer and might play a role in HIV infection and AIDS. In this review, we focus on the interest to build structural model of DARC to understand more precisely its abilities to bind its physiological ligand CXCL8 and its malaria ligand. We also present innovative development on VHHs able to bind DARC protein. We underline difficulties and limitations of such bioinformatics approaches and highlight the crucial importance of biological data to conduct these kinds of researches.
Published: 2010

48. Fast and automated functional classification with MED-SuMo: an application on purine-binding proteins

Author: Doppelt-Azeroual, Olivia, Delfaud, François, Moriaud, Fabrice, de Brevern, Alexandre, Molecular Extended Distribution in Information Technology (MEDIT), MEDIT SA, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by National Institute of Health and Medical Research (INSERM), National Institute of Institute of Blood Transfusion (INTS), University Denis Diderot - Paris 7 and Ministère de la Recherche. ODA‟s PhD is financed by the French technical research association (ANRT) through a CIFRE grant., and de Brevern, Alexandre G.
Subjects: protein kinases, CDK2 and Aurora-A similarity, binding site classification, protein structures, binding sites, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ligand-protein interactions
Abstract: International audience; Ligand-protein interactions are essential for biological processes, and precise characterization of protein binding sites is crucial to understand protein functions. MED-SuMo is a powerful technology to localize similar local regions on protein surfaces. Its heuristic is based on a 3D representation of macromolecules using specific surface chemical features associating chemical characteristics with geometrical properties. MED-SMA is an automated and fast method to classify binding sites. It is based on MED-SuMo technology, which builds a similarity graph, and it uses the Markov Clustering algorithm. Purine binding sites are well studied as drug targets. Here, purine binding sites of the Protein DataBank (PDB) are classified. Proteins potentially inhibited or activated through the same mechanism are gathered. Results are analyzed according to PROSITE annotations and to carefully refined functional annotations extracted from the PDB. As expected, binding sites associated with related mechanisms are gathered, for example, the Small GTPases. Nevertheless, protein kinases from different Kinome families are also found together, for example, Aurora-A and CDK2 proteins which are inhibited by the same drugs. Representative examples of different clusters are presented. The effectiveness of the MED-SMA approach is demonstrated as it gathers binding sites of proteins with similar structure-activity relationships. Moreover, an efficient new protocol associates structures absent of cocrystallized ligands to the purine clusters enabling those structures to be associated with a specific binding mechanism. Applications of this classification by binding mode similarity include target-based drug design and prediction of cross-reactivity and therefore potential toxic side effects.
Published: 2010

49. AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function

Author: Jallu, Vincent, Dusseaux, Mathilde, Panzer, Simon, Torchet, Marie-Françoise, Hezard, Nathalie, Goudemand, Jenny, de Brevern, Alexandre, Kaplan, Cécile, Laboratoire d'immunologie plaquettaire, Institut National de la Transfusion Sanguine [Paris] (INTS), Department of Blood Group Serology and Transfusion Medicine, Medizinische Universität Wien = Medical University of Vienna, Centre des Hémophiles, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Reims Champagne-Ardenne (URCA), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), The work done by M. Dusseaux was supported by a grant from Novo Nordisk, and de Brevern, Alexandre G.
Subjects: MESH: Integrin beta3, alphaIIbbeta3, MESH: Molecular Sequence Data, MESH: Humans, MESH: Alleles, MESH: Alternative Splicing, MESH: Integrin alpha2, MESH: Base Sequence, MESH: Cercopithecus aethiops, MESH: Gene Expression Regulation, MESH: Receptors, Fibrinogen, MESH: Thrombasthenia, MESH: COS Cells, MESH: Structure-Activity Relationship, ITGA2B, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein structure modeling, Glanzmann, MESH: DNA Mutational Analysis, ITGB3
Abstract: International audience; Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation due to defects in integrin alphaIIbbeta3 (ITGA2B, ITGB3), a fibrinogen receptor. Mutations from 24 GT patients and two carriers of various origins, Caucasian, North-African and Asian were characterized. Promoter and exon sequences of alphaIIb and beta3 genes were amplified and directly sequenced. Among 29 identified mutations, 17 new allelic variants resulting from nonsense, missense and deletion/insertion mutations were described. RNA alterations were evaluated by using Web servers. The alphaIIb p.S926L, p.V903F, and beta3 p.C38Y, p.M118R, p.G221D substitutions prevented complex expression at the surface of COS-7 cells by altering the alphaIIb or the beta3 subunit structure. As shown by free energy analyses applied on the resolved structure of alphaIIbbeta3 and structural modeling of the mutant, the p.K253M substitution of beta3 helped to define a key role of the K253 in the interaction of the alphaIIb beta-propeller and the beta3 beta-I domains. finally, the alphaIIb p.Q595H substitution allowed cell surface expression of the complex but its corresponding c.2800G>T mutation is predicted to alter normal RNA splicing. In conclusion, our study yielded the discovery of 17 new GT allelic variants, revealed the key role of K253 of alphaIIb for the alphaIIbbeta3 complex formation and provides an additional example of an apparently missense mutation causing a splicing defect.
Published: 2010

50. Observer avec un nouvel oeil la structure des protéines et leur flexibilité

Author: De Brevern, Alexandre, de Brevern, Alexandre G., Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and French Ministry of Research, University of Paris Diderot - Paris 7, French National Institute for Blood Transfusion (INTS), French National Institute for Health and Medical Research (INSERM).
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], alphabet structural, structures secondaires, cristallographie, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], structure protéique, simulation moléculaire, dynamique moléculaire, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, facteurs B, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Machines à Vecteurs de Supports, Blocs Protéiques, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: National audience; Les structures tridimensionnelles (3D) des protéines sont le support de leurs fonctions biologiques. Pour mieux comprendre les règles gouvernant l'état replié et donc à terme prédire cet état à partir de la séquence, une description fine des structures 3D est nécessaire. Celles-ci sont souvent représentées à l'aide des structures secondaires, les hélices et les feuillets , laissant 50% des résidus affectés à des états non précisément caractérisés, les boucles. Cette simplification ne permet pas de reconstruire la structure 3D. Une vision nouvelle a donc émergé, les alphabets structuraux, ensemble de petits fragments protéiques prototypes qui permettent d'approximer l'ensemble des structures locales des protéines.
Published: 2010

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