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2. Structural Space of the Duffy Antigen/Receptor for Chemokines’ Intrinsically Disordered Ectodomain 1 Explored by Temperature Replica-Exchange Molecular Dynamics Simulations

Author

Agata Kranjc, Tarun Jairaj Narwani, Sophie S. Abby, and Alexandre G. de Brevern

Subjects
chemokine receptors, molecular dynamics, Plasmodium vivax, malaria, protein structures, structural alphabet, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Plasmodium vivax malaria affects 14 million people each year. Its invasion requires interactions between the parasitic Duffy-binding protein (PvDBP) and the N-terminal extracellular domain (ECD1) of the host’s Duffy antigen/receptor for chemokines (DARC). ECD1 is highly flexible and intrinsically disordered, therefore it can adopt different conformations. We computationally modeled the challenging ECD1 local structure. With T-REMD simulations, we sampled its dynamic behavior and collected its most representative conformations. Our results suggest that most of the DARC ECD1 domain remains in a disordered state during the simulated time. Globular local conformations are found in the analyzed local free-energy minima. These globular conformations share an α-helix spanning residues Ser18 to Ser29 and in many cases they comprise an antiparallel β-sheet, whose β-strands are formed around residues Leu10 and Ala49. The formation of a parallel β-sheet is almost negligible. So far, progress in understanding the mechanisms forming the basis of the P. vivax malaria infection of reticulocytes has been hampered by experimental difficulties, along with a lack of DARC structural information. Our collection of the most probable ECD1 structural conformations will help to advance modeling of the DARC structure and to explore DARC–ECD1 interactions with a range of physiological and pathological ligands.

Published
2023
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3. NOD: a web server to predict New use of Old Drugs to facilitate drug repurposing

Author

Tarun Jairaj Narwani, Narayanaswamy Srinivasan, and Sohini Chakraborti

Subjects
Medicine, Science
Abstract

Abstract Computational methods accelerate the drug repurposing pipelines that are a quicker and cost-effective alternative to discovering new molecules. However, there is a paucity of web servers to conduct fast, focussed, and customized investigations for identifying new uses of old drugs. We present the NOD web server, which has the mentioned characteristics. NOD uses a sensitive sequence-guided approach to identify close and distant homologs of a protein of interest. NOD then exploits this evolutionary information to suggest potential compounds from the DrugBank database that can be repurposed against the input protein. NOD also allows expansion of the chemical space of the potential candidates through similarity searches. We have validated the performance of NOD against available experimental and/or clinical reports. In 65.6% of the investigated cases in a control study, NOD is able to identify drugs more effectively than the searches made in DrugBank. NOD is freely-available at http://pauling.mbu.iisc.ac.in/NOD/NOD/ .

Published
2021
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4. Data set of intrinsically disordered proteins analysed at a local protein conformation level

Author

Akhila Melarkode Vattekatte, Tarun Jairaj Narwani, Aline Floch, Mirjana Maljković, Soubika Bisoo, Nicolas K. Shinada, Agata Kranjc, Jean-Christophe Gelly, Narayanaswamy Srinivasan, Nenad Mitić, and Alexandre G. de Brevern

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Science (General), 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
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5. In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Author

Matthieu Goguet, Tarun Jairaj Narwani, Rachel Petermann, Vincent Jallu, and Alexandre G. de Brevern

Subjects
Medicine, Science
Abstract

Abstract Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired αIIbβ3 expression. This method is aimed at studying all αIIbβ3 sub-domains and impact of missense mutations at local and global structural level.

Published
2017
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6. Shaking the β-Bulges

Author

Tarun Jairaj Narwani, Joseph Rebehmed, Narayanaswamy Srinivasan, Alexandre G. de Brevern, Jean-Christophe Gelly, and Pierrick Craveur

Subjects
Chemistry, Protein Conformation, Applied Mathematics, 0206 medical engineering, Proteins, Astrophysics::Cosmology and Extragalactic Astrophysics, 02 engineering and technology, computer.file_format, Protein superfamily, Molecular Dynamics Simulation, Protein Data Bank, Electronic mail, Protein Structure, Secondary, Molecular dynamics, Protein structure, Genetics, Biophysics, Protein Conformation, beta-Strand, Protein crystallization, Beta (finance), computer, Protein secondary structure, Astrophysics::Galaxy Astrophysics, 020602 bioinformatics, Biotechnology
Abstract

bulges are irregularities inside the -sheets. They represent more than 3% of the protein residues, i.e. they are as frequent as 3.10 helices. In terms of evolution, -bulges are not more conserved than any other local protein conformations within homologous protein structures. In a first of its kind study, we have investigated the dynamical behaviour of -bulges using the largest known set of protein molecular dynamics simulations. We observed that more than 50% of the existing -bulges in protein crystal structures remained stable during dynamics while more than1/6th were not stable at all and disappeared entirely. Surprisingly, 1.1% of -bulges that appeared remained stable. -bulges have been categorized in different subtypes. The most common -bulges types are the smallest insertion in -strands (namely AC and AG); they are found as stable as the whole -bulges dataset. Low occurring types (namely PC and AS), that have the largest insertions, are significantly more stable than expected. Thus, this pioneer study allowed to precisely quantify the stability of the -bulges, demonstrating their structural robustness, with few unexpected cases raising structural questions.

Published
2021

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

Author

Narayanaswamy Srinivasan, Tarun Jairaj Narwani, A.G. de Brevern, and R.A. Kalaivani

Subjects
0303 health sciences, Chemistry, Kinase, Protein dynamics, 030302 biochemistry & molecular biology, Substrate (chemistry), Biochemistry, 03 medical and health sciences, Molecular dynamics, Helix, Biophysics, Phosphorylation, Molecule, Protein kinase A, Molecular Biology, 030304 developmental biology
Abstract

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
2018

8. 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

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 structural entropy index to analyse local conformations in intrinsically disordered proteins

Author

Nicolas K. Shinada, Alexandre G. de Brevern, Nenad S. Mitić, Melarkode Vattekatte Akhila, Mirjana Maljković, Agata Kranjc, Tarun Jairaj Narwani, Narayanaswamy Srinivasan, Jean-Christophe Gelly, Soubika Bisoo, Aline Floch, 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), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 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 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)

Subjects
Physics, 0303 health sciences, Structural entropy, Local conformation, Protein Conformation, 030302 biochemistry & molecular biology, Intrinsically disordered proteins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Condensed Matter::Disordered Systems and Neural Networks, Intrinsically Disordered Proteins, flexibility, 03 medical and health sciences, Generalized entropy index, Protein structure, rigidity, Structural Biology, protein structures, Entropy (information theory), structural alphabet, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Structural alphabet, Statistical physics, entropy, 030304 developmental biology
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

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

Author

Frédéric Cadet, Nicolas K. Shinada, Olivier Bertrand, Floriane Noël, Alexandre G. de Brevern, Alain Malpertuy, Jean-Christophe Gelly, Jean-Philippe Meyniel, Tarun Jairaj Narwani, Akhila Melarkode Vattekatte, 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 de Paris (UP), 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)-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), 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
Bioinformatics, Computer science, [SDV]Life Sciences [q-bio], Structural alphabet, In silico, Bioinformatics Keywords Secondary structure, Discrete analysis, lcsh:Medicine, Complementarity determining region, Computational biology, Subjects Biochemistry, Biochemistry, Antibodies, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Secondary structure, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein secondary structure, Complementarity determining regions, 030304 developmental biology, 0303 health sciences, Heavy chain, Frameworks, General Neuroscience, lcsh:R, 030302 biochemistry & molecular biology, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Template, Complementarity (molecular biology), Sequence structure relationship, Nanobodies, General Agricultural and Biological Sciences
Abstract

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 three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain. This feature of the VHH, along with their 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 relationship. In this study, sequence characteristics of VHH domains 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 VHH domains 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

12. 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

13. 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

14. 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

15. Genome sequence and comparative analysis of clavicipitaceous insect-pathogenic fungus Aschersonia badia with Metarhizium spp

Author

Yamini Agrawal, Tarun Jairaj Narwani, and Srikrishna Subramanian

Subjects
0301 basic medicine, Insecta, 030106 microbiology, Virulence, Biology, Genome, Microbiology, 03 medical and health sciences, Ascomycota, Genetics, Animals, Gene family, Destruxin, Gene, Phylogeny, Host-specificity, Whole genome sequencing, Chitinases, Chitinase, Computational Biology, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Genomics, Pathogen-host interactions, Pathogenic fungus, biology.organism_classification, Host-Pathogen Interactions, Mutation, DNA Transposable Elements, Metarhizium, biology.protein, Genome, Fungal, Research Article, Biotechnology
Abstract

Background Aschersonia badia [(Ab) Teleomorph: Hypocrella siamensis] is an entomopathogenic fungus that specifically infects scale insects and whiteflies. We present the whole genome sequence of Ab and its comparison with two clavicipitaceous fungi Metarhizium robertsii (MR: generalist entomopathogen) and M. acridum (MAC: acridid-specific entomopathogen) that exhibit variable host preferences. Here, through comparative analysis of pathogen-host interacting genes, carbohydrate active enzymes, secondary metabolite biosynthesis genes, and sexuality genes, we explore the proteins with possible virulence functions in clavicipitaceous fungi. Comprehensive overview of GH18 family chitinases has been provided to decipher the role of chitinases in claviceptaceous fungi that are either host specific or generalists. Results We report the 28.8 Mb draft genome of Ab and its comparative genome analysis with MR and MAC. The comparative analyses suggests expansion in pathogen-host interacting gene families and carbohydrate active enzyme families in MR, whilst their contraction in Ab and MAC genomes. The multi-modular NRPS gene (dtxS1) responsible for biosynthesis of the secondary metabolite destruxin in MR is not conserved in Ab, similar to the specialist pathogen MAC. An additional siderophore biosynthetic gene responsible for acquisition of iron was identified in MR. Further, the domain survey of chitinases suggest that the CBM50 (LysM) domains, which participate in chitin-binding functions, were not observed in MAC, but were present in Ab and MR. However, apparent differences in frequency of CBM50 domains associated with chitinases of Ab and MR was identified, where MR chitinases displayed a higher proportion of associated CBM50 domains than Ab chitinases. Conclusions This study suggests differences in distribution of dtxS1 and chitinases in specialists (Ab and MAC) and generalists (MR) fungi. Our analysis also suggests the presence of a siderophore biosynthetic gene in the MR genome which perhaps aids in enhanced virulence potential and host range. The variation in association of CBMs, being higher in generalists (MR) and lower in specialists (Ab and MAC) fungi may further be responsible for the differences in host affiliation. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2710-6) contains supplementary material, which is available to authorized users.

Published
2016

16. Complete Genome Sequence and Comparative Genomics of a Novel Myxobacterium Myxococcus hansupus

Author

Gaurav Sharma, Srikrishna Subramanian, and Tarun Jairaj Narwani

Subjects
0301 basic medicine, Proteomes, lcsh:Medicine, Genome, Biochemistry, Database and Informatics Methods, lcsh:Science, Myxococcus xanthus, Myxococcus, Phylogeny, Genetics, Multidisciplinary, biology, Myxococcus Xanthus, Genome project, Genomics, Genomic Databases, Prokaryotic Models, Research Article, food.ingredient, 030106 microbiology, Mycology, Research and Analysis Methods, 03 medical and health sciences, food, Model Organisms, Myxobacteria, Protein Domains, Fungal Genetics, Fungal Genomics, Comparative genomics, Whole genome sequencing, Bacteria, lcsh:R, fungi, Organisms, Biology and Life Sciences, Computational Biology, Proteins, Sequence Analysis, DNA, Comparative Genomics, biology.organism_classification, Genome Analysis, 030104 developmental biology, Biological Databases, bacteria, lcsh:Q, Genome, Bacterial
Abstract

Myxobacteria, a group of Gram-negative aerobes, belong to the class δ-proteobacteria and order Myxococcales. Unlike anaerobic δ-proteobacteria, they exhibit several unusual physiogenomic properties like gliding motility, desiccation-resistant myxospores and large genomes with high coding density. Here we report a 9.5 Mbp complete genome of Myxococcus hansupus that encodes 7,753 proteins. Phylogenomic and genome-genome distance based analysis suggest that Myxococcus hansupus is a novel member of the genus Myxococcus. Comparative genome analysis with other members of the genus Myxococcus was performed to explore their genome diversity. The variation in number of unique proteins observed across different species is suggestive of diversity at the genus level while the overrepresentation of several Pfam families indicates the extent and mode of genome expansion as compared to non-Myxococcales δ-proteobacteria.

Published
2016

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