30 results on '"protein-structure prediction"'
Search Results
2. Molecular architecture and dynamics of SARS-CoV-2 envelope by integrative modeling
- Author
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Pezeshkian, Weria, Grunewald, Fabian, Narykov, Oleksandr, Lu, Senbao, Arkhipova, Valeria, Solodovnikov, Alexey, Wassenaar, Tsjerk A., Marrink, Siewert J., Korkin, Dmitry, Pezeshkian, Weria, Grunewald, Fabian, Narykov, Oleksandr, Lu, Senbao, Arkhipova, Valeria, Solodovnikov, Alexey, Wassenaar, Tsjerk A., Marrink, Siewert J., and Korkin, Dmitry
- Abstract
Despite tremendous efforts, the exact structure of SARS-CoV-2 and related betacoronaviruses remains elusive. SARS-CoV-2 envelope is a key structural component of the virion that encapsulates viral RNA. It is composed of three structural proteins, spike, membrane (M), and envelope, which interact with each other and with the lipids acquired from the host membranes. Here, we developed and applied an integrative multi -scale computational approach to model the envelope structure of SARS-CoV-2 with near atomistic detail, focusing on studying the dynamic nature and molecular interactions of its most abundant, but largely under-studied, M protein. The molecular dynamics simulations allowed us to test the envelope stability under different configurations and revealed that the M dimers agglomerated into large, filament-like, macromolec-ular assemblies with distinct molecular patterns. These results are in good agreement with current experi-mental data, demonstrating a generic and versatile approach to model the structure of a virus de novo.
- Published
- 2023
3. Improved residue contact prediction using support vector machines and a large feature set
- Author
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Cheng, Jianlin and Baldi, Pierre
- Subjects
protein-structure prediction ,automated structure prediction ,neural-networks ,correlated mutations ,interresidue contacts ,distance restraints ,fold recognition ,small number ,information ,maps - Abstract
BackgroundPredicting protein residue-residue contacts is an important 2D prediction task. It is useful for ab initio structure prediction and understanding protein folding. In spite of steady progress over the past decade, contact prediction remains still largely unsolved.ResultsHere we develop a new contact map predictor (SVMcon) that uses support vector machines to predict medium- and long-range contacts. SVMcon integrates profiles, secondary structure, relative solvent accessibility, contact potentials, and other useful features. On the same test data set, SVMcon's accuracy is 4% higher than the latest version of the CMAPpro contact map predictor. SVMcon recently participated in the seventh edition of the Critical Assessment of Techniques for Protein Structure Prediction (CASP7) experiment and was evaluated along with seven other contact map predictors. SVMcon was ranked as one of the top predictors, yielding the second best coverage and accuracy for contacts with sequence separation >= 12 on 13 de novo domains.ConclusionWe describe SVMcon, a new contact map predictor that uses SVMs and a large set of informative features. SVMcon yields good performance on medium- to long-range contact predictions and can be modularly incorporated into a structure prediction pipeline.
- Published
- 2007
4. Ergodicity and model quality in template-restrained canonical and temperature/Hamiltonian replica exchange coarse-grained molecular dynamics simulations of proteins.
- Author
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Karczyńska, Agnieszka S., Czaplewski, Cezary, Krupa, Paweł, Mozolewska, Magdalena A., Joo, Keehyoung, Lee, Jooyoung, and Liwo, Adam
- Subjects
- *
PROTEIN structure , *MOLECULAR dynamics , *HAMILTONIAN systems , *REPLICA techniques (Microscopy) , *LORENTZIAN function - Abstract
Molecular simulations restrained to single or multiple templates are commonly used in protein-structure modeling. However, the restraints introduce additional barriers, thus impairing the ergodicity of simulations, which can affect the quality of the resulting models. In this work, the effect of restraint types and simulation schemes on ergodicity and model quality was investigated by performing template-restrained canonical molecular dynamics (MD), multiplexed replica-exchange molecular dynamics, and Hamiltonian replica exchange molecular dynamics (HREMD) simulations with the coarse-grained UNRES force field on nine selected proteins, with pseudo-harmonic log-Gaussian (unbounded) or Lorentzian (bounded) restraint functions. The best ergodicity was exhibited by HREMD. It has been found that non-ergodicity does not affect model quality if good templates are used to generate restraints. However, when poor-quality restraints not covering the entire protein are used, the improved ergodicity of HREMD can lead to significantly improved protein models. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
5. Retro operation on the Trp-cage miniprotein sequence produces an unstructured molecule capable of folding similar to the original only upon 2,2,2-trifluoroethanol addition.
- Author
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Vymětal, Jiří, Bathula, Sreenivas Reddy, Černý, Jiří, Chaloupková, Radka, Žídek, Lukáš, Sklenář, Vladimír, and Vondrášek, Jiří
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- *
AMINO acid sequence , *MOLECULAR biology , *FLUOROETHANOL , *PROTEIN structure , *CIRCULAR dichroism - Abstract
Amino acid sequence and environment are the most important factors determining the structure, stability and dynamics of proteins. To evaluate their roles in the process of folding, we studied a retroversion of the well-described Trp-cage miniprotein in water and 2,2,2-trifluoroethanol (TFE) solution. We show, by circular dichroism spectroscopy and nuclear magnetic resonance (NMR) measurement, that the molecule has no stable structure under conditions in which the Trp-cage is folded. A detectable stable structure of the retro Trp-cage, with the architecture similar to that of the original Trp-cage, is established only upon addition of TFE to 30% of the total solvent volume. The retro Trp-cage structure shows a completely different pattern of stabilizing contacts between amino acid residues, involving the guanidinium group of arginine and the aromatic group of tryptophan. The commonly used online prediction methods for protein and peptide structures Robetta and PEP-FOLD failed to predict that the retro Trp-cage is unstructured under default prediction conditions. On the other hand, both methods provided structures with a fold similar to those of the experimentally determined NMR structure in water/TFE but with different contacts between amino acids. [ABSTRACT FROM AUTHOR]
- Published
- 2014
6. Prediction and analysis of higher-order coiled-coils: Insights from proteins of the extracellular matrix, tenascins and thrombospondins.
- Author
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Vincent, Thomas L., Woolfson, Derek N., and Adams, Josephine C.
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EXTRACELLULAR matrix proteins , *TENASCIN , *THROMBOSPONDINS , *OLIGOMERIZATION , *CYTOLOGY , *BIOCHEMISTRY - Abstract
Highlights: [•] Coiled coils are abundant domains important for protein–protein oligomerisation. [•] Prediction of their oligomer states remains challenging. [•] We tested the algorithm, LOGICOIL, on coiled-coils from tenascins and thrombospondins. [•] LOGICOIL outperforms current widely used algorithms. [•] Conserved features of trimerising and pentamerising coiled-coils were identified. [Copyright &y& Elsevier]
- Published
- 2013
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7. Whither structural biologists?
- Author
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Kleywegt GJ and Velankar S
- Abstract
The scientific impact of accurate protein-structure prediction methods is being felt already, but how might they affect the work and careers of structural biologists?, (© Kleywegt and Velankar 2022.)
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- 2022
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8. SHARPEN—Systematic Hierarchical Algorithms for Rotamers and Proteins on an Extended Network.
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LOKSHA, ILYA V., MAIOLO III, JAMES R., HONG, CHENG W., NG, ALBERT, and SNOW, CHRISTOPHER D.
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ALGORITHMS , *PROTEINS , *BIOLOGISTS , *COMPUTER software , *HOMOLOGY (Biology) - Abstract
Algorithms for discrete optimization of proteins play a central role in recent advances in protein structure prediction and design. We wish to improve the resources available for computational biologists to rapidly prototype such algorithms and to easily scale these algorithms to many processors. To that end, we describe the implementation and use of two new open source resources, citing potential benefits over existing software. We discuss CHOMP, a new object-oriented library for macromolecular optimization, and SHARPEN, a framework for scaling CHOMP scripts to many computers. These tools allow users to develop new algorithms for a variety of applications including protein repacking, protein–protein docking, loop rebuilding, or homology model remediation. Particular care was taken to allow modular energy function design; protein conformations may currently be scored using either the OPLSaa molecular mechanical energy function or an all-atom semiempirical energy function employed by Rosetta. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]
- Published
- 2009
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9. Kinking the Coiled Coil – Negatively Charged Residues at the Coiled-coil Interface
- Author
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Straussman, Ravid, Ben-Ya’acov, Ami, Woolfson, Derek N., and Ravid, Shoshana
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AMINO acids , *PROTEINS , *GENETIC mutation , *GENETICS - Abstract
Abstract: The coiled coil is one of the most common protein-structure motifs. It is believed to be adopted by 3–5% of all amino acids in proteins. It comprises two or more α-helical chains wrapped around one another. The sequences of most coiled coils are characterized by a seven-residue (heptad) repeat, denoted ( abcdefg ) n . Residues at the a and d positions define the helical interface (core) and are usually hydrophobic, though about 20% are polar or charged. We show that parallel coiled-coils have a unique pattern of their negatively charged residues at the core positions: aspartic acid is excluded from these positions while glutamic acid is not. In contrast the antiparallel structures are more permissive in their amino acid usage. We show further, and for the first time, that incorporation of Asp but not Glu into the a positions of a parallel coiled coil creates a flexible hinge and that the maximal hinge angle is being directly related to the number of incorporated mutations. These new computational and experimental observations will be of use in improving protein-structure predictions, and as rules to guide rational design of novel coiled-coil motifs and coiled coil-based materials. [Copyright &y& Elsevier]
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- 2007
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10. GEM: A Gaussian evolutionary method for predicting protein side-chain conformations.
- Author
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Yang, Jinn-Moon, Tsai, Chi-Hung, Hwang, Ming-Jing, Tsai, Huai-Kuang, Hwang, Jenn-Kang, and Kao, Cheng-Yan
- Abstract
We have developed an evolutionary approach to predicting protein side-chain conformations. This approach, referred to as the Gaussian Evolutionary Method (GEM), combines both discrete and continuous global search mechanisms. The former helps speed up convergence by reducing the size of rotamer space, whereas the latter, integrating decreasing-based Gaussian mutations and self-adaptive Gaussian mutations, continuously adapts dihedrals to optimal conformations. We tested our approach on 38 proteins ranging in size from 46 to 325 residues and showed that the results were comparable to those using other methods. The average accuracies of our predictions were 80% for χ
1 , 66% for χ1 + 2 , and 1.36 Å for the root mean square deviation of side-chain positions. We found that if our scoring function was perfect, the prediction accuracy was also essentially perfect. However, perfect prediction could not be achieved if only a discrete search mechanism was applied. These results suggest that GEM is robust and can be used to examine the factors limiting the accuracy of protein side-chain prediction methods. Furthermore, it can be used to systematically evaluate and thus improve scoring functions. [ABSTRACT FROM AUTHOR]- Published
- 2002
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11. Macromolecular modeling and design in Rosetta: recent methods and frameworks
- Author
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Jack Maguire, Ragul Gowthaman, Marion F. Sauer, Georg Kuenze, Tanja Kortemme, Benjamin Basanta, Indigo Chris King, Jens Meiler, Rhiju Das, Ora Schueler-Furman, Nicholas A. Marze, Brandon Frenz, Christoffer Norn, Julia Koehler Leman, Jason W. Labonte, Kala Bharath Pilla, Lei Shi, Sergey Lyskov, Brian D. Weitzner, Nir London, Karen R. Khar, Jaume Bonet, Nawsad Alam, Andreas Scheck, Alexander M. Sevy, Lars Malmström, Thomas Huber, Christopher Bystroff, Lior Zimmerman, Lorna Dsilva, Bruno E. Correia, Roland L. Dunbrack, Sergey Ovchinnikov, Rocco Moretti, Scott Horowitz, Phil Bradley, Frank DiMaio, Noah Ollikainen, Brian Kuhlman, Jeffrey J. Gray, Melanie L. Aprahamian, Andrew Leaver-Fay, Santrupti Nerli, Brian Koepnick, Xingjie Pan, Manasi A. Pethe, Andrew M. Watkins, Summer B. Thyme, Enrique Marcos, Vikram Khipple Mulligan, Hahnbeom Park, Po-Ssu Huang, David K. Johnson, Daniel-Adriano Silva, Patrick Barth, Shannon Smith, Caleb Geniesse, Jason K. Lai, Patrick Conway, Amelie Stein, Jeliazko R. Jeliazkov, David Baker, Dominik Gront, Kalli Kappel, Firas Khatib, Robert Kleffner, Brian J. Bender, Richard Bonneau, Kyle A. Barlow, Joseph H. Lubin, Shourya S. Roy Burman, Nikolaos G. Sgourakis, Yuval Sedan, Ryan E. Pavlovicz, Kristin Blacklock, Seth Cooper, Barak Raveh, Alisa Khramushin, John Karanicolas, Justin B. Siegel, Sharon L. Guffy, Brian G. Pierce, Alex Ford, Darwin Y. Fu, Orly Marcu, Gideon Lapidoth, Brian Coventry, René M. de Jong, Shane O’Conchúir, Thomas W. Linsky, William R. Schief, Rebecca F. Alford, Scott E. Boyken, Sagar D. Khare, Maria Szegedy, Ray Yu-Ruei Wang, Steven M. Lewis, Hamed Khakzad, Timothy M. Jacobs, Frank D. Teets, Lukasz Goldschmidt, Daisuke Kuroda, Steffen Lindert, P. Douglas Renfrew, Yifan Song, Jared Adolf-Bryfogle, Michael S. Pacella, and Aliza B. Rubenstein
- Subjects
atomic-accuracy ,Models, Molecular ,Computer science ,Macromolecular Substances ,Protein Conformation ,Interoperability ,computational design ,Score ,antibody structures ,Biochemistry ,Article ,homing endonuclease specificity ,03 medical and health sciences ,Software ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,business.industry ,Proteins ,Usability ,fold determination ,Cell Biology ,Molecular Docking Simulation ,variable region ,Docking (molecular) ,protein-structure prediction ,small-molecule docking ,Modeling and design ,Peptidomimetics ,User interface ,Software engineering ,business ,de-novo design ,sparse nmr data ,Biotechnology - Abstract
The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at ., This Perspective reviews tools developed over the past five years in the macromolecular modeling, docking and design software Rosetta.
- Published
- 2019
12. Modeling the Structure, Dynamics, and Transformations of Proteins with the UNRES Force Field.
- Author
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Sieradzan AK, Czaplewski C, Krupa P, Mozolewska MA, Karczyńska AS, Lipska AG, Lubecka EA, Gołaś E, Wirecki T, Makowski M, Ołdziej S, and Liwo A
- Subjects
- Entropy, Molecular Dynamics Simulation, Protein Folding, Proteins, Protein Conformation
- Abstract
The physics-based united-residue (UNRES) model of proteins ( www.unres.pl ) has been designed to carry out large-scale simulations of protein folding. The force field has been derived and parameterized based on the principles of statistical-mechanics, which makes it independent of structural databases and applicable to treat nonstandard situations such as, proteins that contain D-amino-acid residues. Powered by Langevin dynamics and its replica-exchange extensions, UNRES has found a variety of applications, including ab initio and database-assisted protein-structure prediction, simulating protein-folding pathways, exploring protein free-energy landscapes, and solving biological problems. This chapter provides a summary of UNRES and a guide for potential users regarding the application of the UNRES package in a variety of research tasks., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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13. Selective Deamination of Mutagens by a Mycobacterial Enzyme
- Author
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Vandana Gaded and Ruchi Anand
- Subjects
0301 basic medicine ,Identification ,Protein-Structure Prediction ,Evolution ,Superfamily ,Isoguanine ,Mycobacterium smegmatis ,Deamination ,Crystallography, X-Ray ,Biochemistry ,Catalysis ,Antibiotic-Resistance ,Nucleobase ,03 medical and health sciences ,chemistry.chemical_compound ,Guanine deaminase ,Colloid and Surface Chemistry ,Cytidine Deaminase ,Catalytic Domain ,Hydrolase ,Tuberculosis ,Guanine Deaminase ,Crystal-Structure ,Yeast Cytosine Deaminase ,030102 biochemistry & molecular biology ,biology ,Active site ,General Chemistry ,biology.organism_classification ,Enzymes ,030104 developmental biology ,chemistry ,biology.protein ,Cytosine ,Mutagens - Abstract
Structure-based methods are powerful tools that are being exploited to unravel new functions with therapeutic advantage. Here, we report the discovery of a new class of deaminases, predominantly found in mycobacterial species that act on the commercially important s-triazine class of compounds. The enzyme Msd from Mycobacterium smegmatis was taken as a representative candidate from an evolutionarily conserved subgroup that possesses high density of Mycobacterium deaminases. Biochemical investigation reveals that Msd specifically acts on mutagenic nucleobases such as 5-azacytosine and isoguanine and does not accept natural bases as substrates. Determination of the X-ray structure of Msd to a resolution of 1.9 angstrom shows that Msd has fine-tuned its active site such that it is a hybrid of a cytosine as well as a guanine deaminase, thereby conferring Msd the ability to expand its repertoire to both purine and pyrimidine-like mutagens. Mapping of active site residues along with X-ray structures with a series of triazine analogues aids in deciphering the mechanism by which Msd proofreads the base milieu for mutagens. The genome location of the enzyme reveals that Msd is part of a conserved cluster that confers the organism with innate resistance: toward select xenobiotics by triggering their efflux.
- Published
- 2017
14. N-terminomics identifies Prli42 as a membrane miniprotein conserved in Firmicutes and critical for stressosome activation in Listeria monocytogenes
- Author
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Lilliana Radoshevich, Christophe Bécavin, M. Graciela Pucciarelli, Pascale Cossart, Francis Impens, J. R. Mellin, Allison H. Williams, Nathalie Rolhion, Mélodie Duval, Francisco García-del Portillo, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Biocomputing Unit [Madrid], Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], This work was supported by grants to P.C. (European Research Council (ERC) Advanced Grant BacCellEpi (670823), ANR BACNET (BACNET 10-BINF-02-01), ANR Investissement d’Avenir Programme (10-LABX-62-IBEID), Human Frontier Science Program (HFSP, GP001/2013), ERANET Infect-ERA PROANTILIS (ANR-13-IFEC-0004-02) and the Fondation le Roch les Mousquetaires., The authors thank E. Gouin and L. Maranghi for essential technical support, C. O'Byrne and J. Johansson for discussions, C. Thireau for technical support, the Pasteur Ultrapole and C. Rapisarda for help with the EM. The authors thank T. Msadek for providing the L. monocytogenes LO28 ΔclpB strain and the Pasteur Proteomics platform, in particular M. Matondo-Bouzanda and T. Chaze, ANR-10-BINF-0002,BACNET,Exploring composition and dynamics of bacterial regulatory networks(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-13-IFEC-0004,PROANTILIS,Subversive pro- and anti-inflammation trade-offs promote infection by Listeria monocytogenes(2013), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], ANR-10-BINF-02-01/10-BINF-0002,BACNET,BACNET(2010), and ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010)
- Subjects
0301 basic medicine ,Proteomics ,[SDV]Life Sciences [q-bio] ,Mutant ,Bacillus subtilis ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Sigma factor ,Regulation of gene expression ,biology ,TERMINAL PEPTIDES ,Cell biology ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,ESCHERICHIA-COLI ,WEB SERVER ,Pathogens ,Signal Transduction ,Microbiology (medical) ,GRAM-POSITIVE BACTERIA ,Firmicutes ,030106 microbiology ,Immunology ,MOLECULAR ARCHITECTURE ,Bacillus ,Sigma Factor ,ENVIRONMENTAL-STRESS ,Regulon ,Microbiology ,Article ,BACILLUS-SUBTILIS ,03 medical and health sciences ,Bacterial Proteins ,Listeria monocytogenes ,Stress, Physiological ,Genetics ,medicine ,PROTEIN-STRUCTURE PREDICTION ,DIAGONAL CHROMATOGRAPHY ,Membranes ,Biology and Life Sciences ,Gene Expression Regulation, Bacterial ,Cell Biology ,biology.organism_classification ,030104 developmental biology ,VIRULENCE ,Protein Processing, Post-Translational ,Genome, Bacterial - Abstract
International audience; To adapt to changing environments, bacteria have evolved numerous pathways that activate stress response genes. In Gram-positive bacteria, the stressosome, a cytoplasmic complex, relays external cues and activates the sigma B regulon. The stressosome is structurally well-characterized in Bacillus, but how it senses stress remains elusive. Here, we report a genome-wide N-terminomic approach in Listeria that strikingly led to the discovery of 19 internal translation initiation sites and 6 miniproteins, among which one, Prli42, is conserved in Firmicutes. Prli42 is membrane-anchored and interacts with orthologues of Bacillus stressosome components. We reconstituted the Listeria stressosome in vitro and visualized its supramolecular structure by electron microscopy. Analysis of a series of Prli42 mutants demonstrated that Prli42 is important for sigma B activation, bacterial growth following oxidative stress and for survival in macrophages. Taken together, our N-terminonic approach unveiled Prli42 as a long-sought link between stress and the stressosome.
- Published
- 2017
15. CorNet: Assigning function to networks of co-evolving residues by automated literature mining
- Author
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Tom Desmet, Bas Vroling, Alberto Nobili, Peter J. Schaap, Tom van den Bergh, Uwe T. Bornscheuer, Yifeng Tao, Bernd Nidetzky, René M. de Jong, Gert Vriend, Kalyanasundaram Subramanian, Tianwei Tan, Henk-Jan Joosten, Remko Kuipers, and Giorgio E. Tamò
- Subjects
0301 basic medicine ,Models, Molecular ,Protein Structure Comparison ,ALIGNMENTS ,Protein Conformation ,Hydrolases ,Mutant ,lcsh:Medicine ,Protein Structure Prediction ,01 natural sciences ,Biochemistry ,FAMILIES ,Automation ,Database and Informatics Methods ,Protein structure ,Microbiologie ,Macromolecular Structure Analysis ,Data Mining ,Systems and Synthetic Biology ,Amino Acids ,lcsh:Science ,Mathematics ,Systeem en Synthetische Biologie ,Multidisciplinary ,OCEAN SAMPLING EXPEDITION ,Organic Compounds ,Esterases ,SUPERFAMILY ,Protein structure prediction ,Directed evolution ,FLUORESCENS ,Enzymes ,Chemistry ,CORRELATED MUTATION ANALYSES ,Physical Sciences ,Sequence Analysis ,Research Article ,Multiple Alignment Calculation ,Protein Structure ,Proline ,Bioinformatics ,DIRECTED EVOLUTION ,Sequence alignment ,Computational biology ,ENANTIOSELECTIVITY ,Research and Analysis Methods ,Microbiology ,Evolution, Molecular ,03 medical and health sciences ,Computational Techniques ,Life Science ,PROTEIN-STRUCTURE PREDICTION ,Protein structure comparison ,Molecular Biology ,VLAG ,Internet ,IDENTIFICATION ,010405 organic chemistry ,lcsh:R ,Organic Chemistry ,Chemical Compounds ,Computational Biology ,Proteins ,Biology and Life Sciences ,Cyclic Amino Acids ,Split-Decomposition Method ,0104 chemical sciences ,030104 developmental biology ,Proteins metabolism ,Alcohols ,Mutation ,Enzymology ,lcsh:Q ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Sequence Alignment - Abstract
Contains fulltext : 174131.pdf (Publisher’s version ) (Open Access) CorNet is a web-based tool for the analysis of co-evolving residue positions in protein super-family sequence alignments. CorNet projects external information such as mutation data extracted from literature on interactively displayed groups of co-evolving residue positions to shed light on the functions associated with these groups and the residues in them. We used CorNet to analyse six enzyme super-families and found that groups of strongly co-evolving residues tend to consist of residues involved in a same function such as activity, specificity, co-factor binding, or enantioselectivity. This finding allows to assign a function to residues for which no data is available yet in the literature. A mutant library was designed to mutate residues observed in a group of co-evolving residues predicted to be involved in enantioselectivity, but for which no literature data is available yet. The resulting set of mutations indeed showed many instances of increased enantioselectivity.
- Published
- 2017
16. Identification of Function and Mechanistic Insights of Guanine Deaminase from Nitrosomonas europaea: Role of the C-Terminal Loop in Catalysis
- Author
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Ruchi Anand, Ajay Singh Tanwar, Aruna Bitra, and Bhukya Hussain
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Models, Molecular ,Protein-Structure Prediction ,Adenosine ,Mouse ,Protein Conformation ,Evolution ,Stereochemistry ,3-Dimensional Structure ,Deamination ,Nitrosomonas europaea ,Cytidine ,Ligands ,Biochemistry ,Catalysis ,Substrate Specificity ,Terminal loop ,Guanine deaminase ,Protein structure ,Bacterial Proteins ,Catalytic Domain ,Hydrolase ,Guanine Deaminase ,Crystal-Structure ,Yeast Cytosine Deaminase ,biology ,Chemistry ,Active site ,Substrate (chemistry) ,Serum Guanase ,biology.organism_classification ,Crystallography ,Enzyme ,biology.protein - Abstract
NE0047 from Nitrosomonas europaea has been annotated as a zinc-dependent deaminase; however, the substrate specificity is unknown because of the low level of structural similarity and sequence identity compared to other family members. In this study, the function of NE0047 was established as a guanine deaminase (catalytic efficiency of 1.2 X 10(5) M-1 s(-1)), exhibiting secondary activity towards ammeline. The structure of NE0047 in the presence of the substrate analogue 8-azaguanine was also determined to a resolution of 1.9 angstrom. NE0047 crystallized as a homodimer in an asymmetric unit. It was found that the extreme nine-amino acid C-terminal loop forms an active site flap; in one monomer, the flap is in the closed conformation and in the other in the open conformation with this loop region exposed to the solvent. Calorimetric data obtained using the full-length version of the enzyme fit to a sequential binding model, thus supporting a cooperative mode of ligand occupancy. In contrast, the mutant form of the enzyme (Delta C) with the deletion of the extreme nine amino acids follows an independent model of ligand occupancy. In addition, the Delta C mutant also does not exhibit any enzyme activity. Therefore, we propose that the progress of the reaction is communicated via changes in the conformation of the C-terminal flap and the closed form of the enzyme is the catalytically active form, while the open form allows for product release. The catalytic mechanism of deamination was also investigated, and we found that the mutagenesis of the highly conserved active site residues Glu79 and Glu143 resulted in a complete loss of activity and concluded that they facilitate the reaction by serving as proton shuttles.
- Published
- 2013
17. Mimicking the action of folding chaperones by Hamiltonian replica-exchange molecular dynamics simulations
- Subjects
POTENTIALS ,GROMACS ,statistical potential ,replica-exchange molecular dynamics ,protein structure prediction ,SECONDARY STRUCTURES ,ENHANCEMENT ,protein structure refinement ,MONTE-CARLO ,DESIGN ,FORCE-FIELD ,chaperone ,PROTEIN-STRUCTURE PREDICTION ,ALGORITHM ,ENERGY LANDSCAPE - Abstract
The efficiency of using a variant of Hamiltonian replica-exchange molecular dynamics (Chaperone H-replica-exchange molecular dynamics [CH-REMD]) for the refinement of protein structural models generated de novo is investigated. In CH-REMD, the interaction between the protein and its environment, specifically, the electrostatic interaction between the protein and the solvating water, is varied leading to cycles of partial unfolding and refolding mimicking some aspects of folding chaperones. In 10 of the 15 cases examined, the CH-REMD approach sampled structures in which the root-mean-square deviation (RMSD) of secondary structure elements (SSE-RMSD) with respect to the experimental structure was more than 1.0 angstrom lower than the initial de novo model. In 14 of the 15 cases, the improvement was more than 0.5 angstrom. The ability of three different statistical potentials to identify near-native conformations was also examined. Little correlation between the SSE-RMSD of the sampled structures with respect to the experimental structure and any of the scoring functions tested was found. The most effective scoring function tested was the DFIRE potential. Using the DFIRE potential, the SSE-RMSD of the best scoring structures was on average 0.3 angstrom lower than the initial model. Overall the work demonstrates that targeted enhanced-sampling techniques such as CH-REMD can lead to the systematic refinement of protein structural models generated de novo but that improved potentials for the identification of near-native structures are still needed. Proteins 2012; (c) 2012 Wiley Periodicals, Inc.
- Published
- 2012
18. Refining homology models by combining replica-exchange molecular dynamics and statistical potentials
- Subjects
homology modeling ,structure refinement ,MEAN FORCE ,statistical potential ,HIDDEN MARKOV-MODELS ,replica-exchange molecular dynamics ,protein structure prediction ,SEQUENCE PROFILES ,FOLD-RECOGNITION ,FORCE-FIELD ,PROTEIN-STRUCTURE PREDICTION ,HYDROPEROXIDE RESISTANCE PROTEIN ,GENERALIZED BORN MODELS ,GAS REFERENCE STATE ,HIGH-RESOLUTION REFINEMENT - Abstract
A protocol is presented for the global refinement of homology models of proteins. It combines the advantages of temperature-based replica-exchange molecular dynamics (REMD) for conformational sampling and the use of statistical potentials for model selection. The protocol was tested using 21 models. Of these 14 were models of 10 small proteins for which high-resolution crystal structures were available, the remainder were targets of the recent CASPR exercise. It was found that REMD in combination with currently available force fields could sample near-native conformational states starting from high-quality homology models. Conformations in which the backbone RMSD of secondary structure elements (SSE-RMSD) was lower than the starting value by 0.5-1.0 angstrom were found for 15 out of the 21 cases (average 0.82 angstrom). Furthermore, when a simple scoring function consisting of two statistical potentials was used to rank the structures, one or more structures with SSE-RMSD of at least 0.2 angstrom lower than the starting valise was found among the five best ranked structures in 11 out of the 21 cases. The average improvement in SSE-RMSD for the best models was 0.42 angstrom. However, none of the scoring functions tested identified the structures with the lowest SSE-RMSD as the best models although all identified the native conformation as the one with lowest energy. This suggests that while the proposed protocol proved effective for the refinement of high-quality models of small proteins scoring functions remain one of the major limiting factors in structure refinement. This and other aspects by which the methodology could be further improved are discussed.
- Published
- 2008
19. Using structure to inform carbohydrate binding module function
- Author
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Alicia Lammerts van Bueren, D. Wade Abbott, and Host-Microbe Interactions
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Models, Molecular ,ALPHA-AMYLASE ,Carbohydrates ,POLYSACCHARIDE RECOGNITION ,Computational biology ,Plasma protein binding ,Biology ,Conserved sequence ,2 FAMILIES ,Structural Biology ,Models ,PROTEIN-STRUCTURE PREDICTION ,CRYSTAL-STRUCTURES ,Binding site ,Molecular Biology ,Conserved Sequence ,Phylogeny ,COMPLEX ,Binding Sites ,Molecular Structure ,LIGAND-BINDING ,Protein primary structure ,Molecular ,Proteins ,Protein structure prediction ,Enzymes ,Biochemistry ,STARCH ,Sequence space (evolution) ,Carbohydrate-binding module ,Function (biology) ,CLOSTRIDIUM-PERFRINGENS ,Protein Binding - Abstract
Generally, non-catalytic carbohydrate binding module (CBM) specificity has been shown to parallel the catalytic activity of the carbohydrate active enzyme (CAZyme) module it is appended to. With the rapid expansion in metagenomic sequence space for the potential discovery of new CBMs in addition to the recent emergence of several new CBM families that display diverse binding profiles and novel functions, elucidating the function of these protein modules has become a much more challenging task. This review summarizes several approaches that have been reported for using primary structure to inform CBM specificity and streamlining their biophysical characterization. In addition we discuss general trends in binding site architecture and several newly identified functions for CBMs. Streams of investigation that will facilitate the development and refinement of sequence-based prediction tools are suggested.
- Published
- 2014
20. Molecular Characterization of an NADPH-Dependent Acetoin Reductase/2,3-Butanediol Dehydrogenase from Clostridium beijerinckii NCIMB 8052
- Author
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John Raedts, John van der Oost, Marco A. J. Siemerink, Mark Levisson, and Servé W. M. Kengen
- Subjects
Models, Molecular ,Protein Conformation ,Coenzymes ,Gene Expression ,Dehydrogenase ,Applied Microbiology and Biotechnology ,thermoanaerobacter-brockii ,Substrate Specificity ,sulfolobus-solfataricus ,chemistry.chemical_compound ,Microbiologie ,butanol fer ,Enzyme Stability ,3r)-2 ,(2r ,Cloning, Molecular ,Butylene Glycols ,Clostridium beijerinckii ,chemistry.chemical_classification ,Ecology ,biology ,Acetoin ,Temperature ,Hydrogen-Ion Concentration ,Recombinant Proteins ,Zinc ,Biochemistry ,protein-structure prediction ,l-threonine dehydrogenase ,Biotechnology ,Molecular Sequence Data ,Microbiology ,(2r,3r)-2,3-butanediol dehydrogenase ,Cofactor ,meso-2,3-butanediol dehydrogenase ,L-threonine dehydrogenase ,Escherichia coli ,2,3-Butanediol ,Amino Acid Sequence ,Enzymology and Protein Engineering ,3-butanediol dehydrogenase ,VLAG ,alcohol dehydrogenases ,Substrate (chemistry) ,crystal-structure ,biology.organism_classification ,Alcohol Oxidoreductases ,Enzyme ,chemistry ,biology.protein ,escherichia-coli ,Protein Multimerization ,Sequence Alignment ,meso-2 ,NADP ,Food Science - Abstract
Acetoin reductase is an important enzyme for the fermentative production of 2,3-butanediol, a chemical compound with a very broad industrial use. Here, we report on the discovery and characterization of an acetoin reductase from Clostridium beijerinckii NCIMB 8052. An in silico screen of the C. beijerinckii genome revealed eight potential acetoin reductases. One of them ( CBEI_1464 ) showed substantial acetoin reductase activity after expression in Escherichia coli . The purified enzyme ( C. beijerinckii acetoin reductase [Cb-ACR]) was found to exist predominantly as a homodimer. In addition to acetoin (or 2,3-butanediol), other secondary alcohols and corresponding ketones were converted as well, provided that another electronegative group was attached to the adjacent C-3 carbon. Optimal activity was at pH 6.5 (reduction) and 9.5 (oxidation) and around 68°C. Cb-ACR accepts both NADH and NADPH as electron donors; however, unlike closely related enzymes, NADPH is preferred ( K m , 32 μM). Cb-ACR was compared to characterized close homologs, all belonging to the “threonine dehydrogenase and related Zn-dependent dehydrogenases” (COG1063). Metal analysis confirmed the presence of 2 Zn 2+ atoms. To gain insight into the substrate and cofactor specificity, a structural model was constructed. The catalytic zinc atom is likely coordinated by Cys 37 , His 70 , and Glu 71 , while the structural zinc site is probably composed of Cys 100 , Cys 103 , Cys 106 , and Cys 114 . Residues determining NADP specificity were predicted as well. The physiological role of Cb-ACR in C. beijerinckii is discussed.
- Published
- 2014
21. Enterococcal Rgg-Like Regulator ElrR Activates Expression of the elrA Operon
- Author
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Francis Repoila, Maurizio Sanguinetti, Riccardo Torelli, Romain Dumoulin, Naima G. Cortes-Perez, Brunella Posteraro, Philippe Duhutrel, Sophie Brinster, Pascale Serror, Stéphane Gaubert, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Inst Microbiol, Università cattolica del Sacro Cuore [Milano] (Unicatt), Inst Hyg, Region Ile-de-France, and Università Cattolica del Sacro Cuore
- Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences ,GRAM-POSITIVE BACTERIA ,Operon ,STREPTOCOCCUS-PYOGENES ,TRANSCRIPTIONAL REGULATOR ,Regulator ,Virulence ,lac operon ,Microbiology ,Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA ,Enterococcus faecalis ,Mice ,03 medical and health sciences ,Bacterial Proteins ,MOLECULAR-BASIS ,Animals ,PROTEIN-STRUCTURE PREDICTION ,LACTOCOCCUS-LACTIS ,LISTERIA-MONOCYTOGENES ,Molecular Biology ,Gene ,IN-VIVO ,030304 developmental biology ,Regulator gene ,Genetics ,0303 health sciences ,biology ,030306 microbiology ,Articles ,Gene Expression Regulation, Bacterial ,biology.organism_classification ,SPEB EXPRESSION ,biology.protein ,Glucosyltransferase ,VIRULENCE REGULATOR - Abstract
The Enterococcus faecalis leucine-rich protein ElrA promotes virulence by stimulating bacterial persistence in macrophages and production of the interleukin-6 (IL-6) cytokine. The ElrA protein is encoded within an operon that is poorly expressed under laboratory conditions but induced in vivo . In this study, we identify ef2687 (renamed elrR ), which encodes a member of the Rgg ( r egulator g ene for g lucosyltransferase) family of putative regulatory proteins. Using quantitative reverse transcription-PCR, translational lacZ fusions, and electrophoretic mobility shift assays, we demonstrate that ElrR positively regulates expression of elrA . These results correlate with the attenuated virulence of the Δ elrR strain in a mouse peritonitis model. Virulence of simple and double elrR and elrA deletion mutants also suggests a remaining ElrR-independent expression of elrA in vivo and additional virulence-related genes controlled by ElrR.
- Published
- 2013
22. Mimicking the action of folding chaperones by Hamiltonian replica-exchange molecular dynamics simulations: Application in the refinement of de novo models
- Author
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Fan, Hao, Periole, Xavier, Mark, Alan E., Zernike Institute for Advanced Materials, and Groningen Biomolecular Sciences and Biotechnology
- Subjects
POTENTIALS ,GROMACS ,statistical potential ,replica-exchange molecular dynamics ,protein structure prediction ,SECONDARY STRUCTURES ,ENHANCEMENT ,protein structure refinement ,MONTE-CARLO ,DESIGN ,FORCE-FIELD ,chaperone ,PROTEIN-STRUCTURE PREDICTION ,ALGORITHM ,ENERGY LANDSCAPE - Abstract
The efficiency of using a variant of Hamiltonian replica-exchange molecular dynamics (Chaperone H-replica-exchange molecular dynamics [CH-REMD]) for the refinement of protein structural models generated de novo is investigated. In CH-REMD, the interaction between the protein and its environment, specifically, the electrostatic interaction between the protein and the solvating water, is varied leading to cycles of partial unfolding and refolding mimicking some aspects of folding chaperones. In 10 of the 15 cases examined, the CH-REMD approach sampled structures in which the root-mean-square deviation (RMSD) of secondary structure elements (SSE-RMSD) with respect to the experimental structure was more than 1.0 angstrom lower than the initial de novo model. In 14 of the 15 cases, the improvement was more than 0.5 angstrom. The ability of three different statistical potentials to identify near-native conformations was also examined. Little correlation between the SSE-RMSD of the sampled structures with respect to the experimental structure and any of the scoring functions tested was found. The most effective scoring function tested was the DFIRE potential. Using the DFIRE potential, the SSE-RMSD of the best scoring structures was on average 0.3 angstrom lower than the initial model. Overall the work demonstrates that targeted enhanced-sampling techniques such as CH-REMD can lead to the systematic refinement of protein structural models generated de novo but that improved potentials for the identification of near-native structures are still needed. Proteins 2012; (c) 2012 Wiley Periodicals, Inc.
- Published
- 2012
23. Common and distant structural characteristics of Feruloyl esterase families from Aspergillus oryzae
- Author
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Gianni Panagiotou, Valeria Mapelli, Lisbeth Olsson, D.B.R.K. Gupta Udatha, Udatha, D, Mapelli, V, Panagiotou, G, and Olsson, L
- Subjects
Pectin ,Applied Microbiology ,Aspergillus oryzae ,SECONDARY-STRUCTURE ,Fungal Protein ,Gene Expression ,lcsh:Medicine ,Yeast and Fungal Models ,Plant Science ,Biochemistry ,3-DIMENSIONAL PROFILES ,Substrate Specificity ,chemistry.chemical_compound ,ANALOGOUS ENZYMES ,Feruloyl esterase ,Carboxylic Ester Hydrolases - Chemistry ,CIRCULAR-DICHROISM SPECTRA ,Molecular Cell Biology ,Macromolecular Structure Analysis ,Lignin ,lcsh:Science ,chemistry.chemical_classification ,Fungal protein ,Multidisciplinary ,biology ,food and beverages ,Recombinant Proteins ,Enzymes ,ENZYME EVOLUTION ,Pharmacophore ,Research Article ,Biotechnology ,Protein Structure ,food.ingredient ,Molecular Sequence Data ,Plant Pathogens ,BIOLOGY ,3 DIMENSIONS ,PENICILLIUM-EXPANSUM ,Fungal Proteins ,Structure-Activity Relationship ,food ,Model Organisms ,Carboxylic Ester Hydrolase ,Aspergillus Oryzae - Enzymology ,PROTEIN-STRUCTURE PREDICTION ,Hemicellulose ,Amino Acid Sequence ,Biology ,Fungal Proteins - Chemistry ,lcsh:R ,Proteins ,Computational Biology ,Plant Pathology ,biology.organism_classification ,Enzyme ,chemistry ,SIGNAL PEPTIDES ,I-TASSER ,Enzyme Structure ,lcsh:Q ,Carboxylic Ester Hydrolases - Abstract
Background: Feruloyl esterases (FAEs) are important biomass degrading accessory enzymes due to their capability of cleaving the ester links between hemicellulose and pectin to aromatic compounds of lignin, thus enhancing the accessibility of plant tissues to cellulolytic and hemicellulolytic enzymes. FAEs have gained increased attention in the area of biocatalytic transformations for the synthesis of value added compounds with medicinal and nutritional applications. Following the increasing attention on these enzymes, a novel descriptor based classification system has been proposed for FAEs resulting into 12 distinct families and pharmacophore models for three FAE sub-families have been developed. Methodology/Principal Findings: The feruloylome of Aspergillus oryzae contains 13 predicted FAEs belonging to six sub-families based on our recently developed descriptor-based classification system. The three-dimensional structures of the 13 FAEs were modeled for structural analysis of the feruloylome. The three genes coding for three enzymes, viz., A.O.2, A.O.8 and A.O.10 from the feruloylome of A. oryzae, representing sub-families with unknown functional features, were heterologously expressed in Pichia pastoris, characterized for substrate specificity and structural characterization through CD spectroscopy. Common feature-based pharamacophore models were developed according to substrate specificity characteristics of the three enzymes. The active site residues were identified for the three expressed FAEs by determining the titration curves of amino acid residues as a function of the pH by applying molecular simulations. Conclusions/Significance: Our findings on the structure-function relationships and substrate specificity of the FAEs of A. oryzae will be instrumental for further understanding of the FAE families in the novel classification system. The developed pharmacophore models could be applied for virtual screening of compound databases for short listing the putative substrates prior to docking studies or for post-processing docking results to remove false positives. Our study exemplifies how computational predictions can complement to the information obtained through experimental methods. © 2012 Udatha et al., published_or_final_version
- Published
- 2012
24. Common and Distant Structural Characteristics of Feruloyl Esterase Families from Aspergillus oryzae
- Author
-
Udatha, D. B. R. K. Gupta, Mapelli, Valeria, Panagiotou, Gianni, Olsson, Lisbeth, Udatha, D. B. R. K. Gupta, Mapelli, Valeria, Panagiotou, Gianni, and Olsson, Lisbeth
- Abstract
Background: Feruloyl esterases (FAEs) are important biomass degrading accessory enzymes due to their capability of cleaving the ester links between hemicellulose and pectin to aromatic compounds of lignin, thus enhancing the accessibility of plant tissues to cellulolytic and hemicellulolytic enzymes. FAEs have gained increased attention in the area of biocatalytic transformations for the synthesis of value added compounds with medicinal and nutritional applications. Following the increasing attention on these enzymes, a novel descriptor based classification system has been proposed for FAEs resulting into 12 distinct families and pharmacophore models for three FAE sub-families have been developed. Methodology/Principal Findings: The feruloylome of Aspergillus oryzae contains 13 predicted FAEs belonging to six subfamilies based on our recently developed descriptor-based classification system. The three-dimensional structures of the 13 FAEs were modeled for structural analysis of the feruloylome. The three genes coding for three enzymes, viz., A.O.2, A.O.8 and A.O.10 from the feruloylome of A. oryzae, representing sub-families with unknown functional features, were heterologously expressed in Pichia pastoris, characterized for substrate specificity and structural characterization through CD spectroscopy. Common feature-based pharamacophore models were developed according to substrate specificity characteristics of the three enzymes. The active site residues were identified for the three expressed FAEs by determining the titration curves of amino acid residues as a function of the pH by applying molecular simulations. Conclusions/Significance: Our findings on the structure-function relationships and substrate specificity of the FAEs of A. oryzae will be instrumental for further understanding of the FAE families in the novel classification system. The developed pharmacophore models could be applied for virtual screening of compound databases for short listing the putati
- Published
- 2012
25. Completion and refinement of 3-D homology models with restricted molecular dynamics: application to targets 47, 58, and 111 in the CASP modeling competition and posterior analysis
- Author
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J.A. Flohil, Gerrit Vriend, Hjc Berendsen, Groningen Biomolecular Sciences and Biotechnology, and Molecular Dynamics
- Subjects
Models, Molecular ,Quality Control ,Protein Folding ,Correctness ,Computer science ,DATABASE ,Bioinformatics ,Molecular Sequence Data ,Non-equilibrium thermodynamics ,Biochemistry ,SEQUENCE ,Molecular dynamics ,Software ,Imaging, Three-Dimensional ,Structural Biology ,Sequence Analysis, Protein ,QUALITY ,Computer Simulation ,PROTEIN-STRUCTURE PREDICTION ,Amino Acid Sequence ,CASP ,Molecular Biology ,Simulation ,Sequence Homology, Amino Acid ,business.industry ,Computational Biology ,Proteins ,Structure validation ,Hydrogen Bonding ,Protein structure prediction ,SIMULATIONS ,Mutagenesis, Insertional ,ALIGNMENT ,Compact space ,business ,Algorithm ,GENERALIZED BORN MODEL - Abstract
Contains fulltext : 186518.pdf (Publisher’s version ) (Closed access) A method is presented to refine models built by homology by the use of restricted molecular dynamics (MD) techniques. The basic idea behind this method is the use of structure validation software to determine for each residue the likelihood that it is modeled correctly. This information is used to determine constraints and restraints in an MD simulation including explicit solvent molecules, which is used for model refinement. The procedure is based on the idea that residues that the validation software identifies as correctly positioned should be strongly constrained or restrained in the MD simulations, whereas residues that are likely to be positioned wrongly should move freely. Two different protocols are compared: one (applied to CASP3 target T58) using full structural constraints with separate optimization of each short fragment and the other (applied to T47) allowing some freedom using harmonic restraining potentials, with automatic optimization of the whole molecule. Structures along the MD trajectory that scored best in structural checks were selected for the construction of models that appeared to be successful in the CASP3 competition. Model refinement with MD in general leads to a model that is less like the experimental structure (Levitt et al. Nature Struct Biol 1999;6:108-111). Actually, refined T47 was slightly improved compared to the starting model; changes in model T58 led not to further enhancement. After the X-ray structure of the modeled proteins became known, the procedure was evaluated for two targets (T47 and the CASP4 target T111) by comparing a long simulation in water with the experimental target structures. It was found that structural improvements could be obtained on a nanosecond time scale by allowing appropriate freedom in the simulation. Structural checks applied to fast fluctuations do not appear to be informative for the correctness of the structure. However, both a simple hydrogen bond count and a simple compactness measure, if averaged over times of typically 300 ps, correlate well with structural correctness and we suggest that criteria based on these properties may be used in computational folding strategies.
- Published
- 2002
26. Retro operation on the Trp-cage miniprotein sequence produces an unstructured molecule capable of folding similar to the original only upon 2,2,2-trifluoroethanol addition.
- Author
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Vymětal J, Bathula SR, Cerný J, Chaloupková R, Zídek L, Sklenář V, and Vondrášek J
- Subjects
- Amino Acid Sequence, Molecular Dynamics Simulation, Molecular Sequence Data, Peptides chemical synthesis, Protein Folding, Protein Stability, Protein Structure, Secondary, Static Electricity, Thermodynamics, Water chemistry, Arginine chemistry, Peptides chemistry, Trifluoroethanol chemistry, Tryptophan chemistry
- Abstract
Amino acid sequence and environment are the most important factors determining the structure, stability and dynamics of proteins. To evaluate their roles in the process of folding, we studied a retroversion of the well-described Trp-cage miniprotein in water and 2,2,2-trifluoroethanol (TFE) solution. We show, by circular dichroism spectroscopy and nuclear magnetic resonance (NMR) measurement, that the molecule has no stable structure under conditions in which the Trp-cage is folded. A detectable stable structure of the retro Trp-cage, with the architecture similar to that of the original Trp-cage, is established only upon addition of TFE to 30% of the total solvent volume. The retro Trp-cage structure shows a completely different pattern of stabilizing contacts between amino acid residues, involving the guanidinium group of arginine and the aromatic group of tryptophan. The commonly used online prediction methods for protein and peptide structures Robetta and PEP-FOLD failed to predict that the retro Trp-cage is unstructured under default prediction conditions. On the other hand, both methods provided structures with a fold similar to those of the experimentally determined NMR structure in water/TFE but with different contacts between amino acids., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
- Full Text
- View/download PDF
27. Computational Complexity of a Problem in Molecular-Structure Prediction
- Author
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Ngo, J. Thomas and Marks, Joe
- Subjects
intractability ,NP-completeness ,peptide backbone conformation ,potential-energy minimization ,protein-structure prediction - Abstract
The computational task of protein-structure prediction is believed to require exponential time, but previous arguments as to its intractability have taken into account only the size of a protein’s conformational space. Such arguments do not rule out the possible existence of an algorithm, more selective than exhaustive search, that is efficient and exact. (An efficient algorithm is one that is guaranteed, for all possible inputs, to run in time bounded by a function polynomial in the problem size. An intractable problem is one for which no efficient algorithm exists.) Questions regarding the possible intractability of problems are often best answered using the theory of NP-completeness. In this treatment we show the NP-hardness of two typical mathematical statements of empirical potential-energy-function minimization for macromolecules. Unless all NP-complete problems can be solved efficiently, these results imply that a function-minimization algorithm can be efficient for protein-structure prediction only if it exploits protein-specific properties that prohibit the simple geometric constructions that we use in our proofs. Analysis of further mathematical statements of molecular-structure prediction could constitute a systematic methodology for identifying sources of complexity in protein folding, and for guiding development of predictive algorithms., Engineering and Applied Sciences
- Published
- 1991
28. Improved residue contact prediction using support vector machines and a large feature set
- Author
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Jianlin Cheng and Pierre Baldi
- Subjects
Models, Molecular ,automated structure prediction ,Computer science ,computer.software_genre ,Biochemistry ,information ,Pattern Recognition, Automated ,Structural Biology ,Protein methods ,Sequence Analysis, Protein ,Protein Interaction Mapping ,Physical Sciences and Mathematics ,small number ,Amino Acids ,Feature set ,Databases, Protein ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,0303 health sciences ,Artificial neural network ,Applied Mathematics ,maps ,030302 biochemistry & molecular biology ,Life Sciences ,fold recognition ,Protein structure prediction ,Amino acid ,Computer Science Applications ,lcsh:R858-859.7 ,protein-structure prediction ,Protein folding ,DNA microarray ,distance restraints ,Algorithm ,Algorithms ,Research Article ,Protein Binding ,neural-networks ,Protein contact map ,Sequence alignment ,lcsh:Computer applications to medicine. Medical informatics ,Machine learning ,03 medical and health sciences ,Artificial Intelligence ,Computer Simulation ,Binding site ,Molecular Biology ,030304 developmental biology ,Binding Sites ,interresidue contacts ,business.industry ,Proteins ,Support vector machine ,lcsh:Biology (General) ,chemistry ,Models, Chemical ,Artificial intelligence ,Threading (protein sequence) ,business ,computer ,Sequence Alignment ,Test data ,correlated mutations - Abstract
Background Predicting protein residue-residue contacts is an important 2D prediction task. It is useful for ab initio structure prediction and understanding protein folding. In spite of steady progress over the past decade, contact prediction remains still largely unsolved. Results Here we develop a new contact map predictor (SVMcon) that uses support vector machines to predict medium- and long-range contacts. SVMcon integrates profiles, secondary structure, relative solvent accessibility, contact potentials, and other useful features. On the same test data set, SVMcon's accuracy is 4% higher than the latest version of the CMAPpro contact map predictor. SVMcon recently participated in the seventh edition of the Critical Assessment of Techniques for Protein Structure Prediction (CASP7) experiment and was evaluated along with seven other contact map predictors. SVMcon was ranked as one of the top predictors, yielding the second best coverage and accuracy for contacts with sequence separation >= 12 on 13 de novo domains. Conclusion We describe SVMcon, a new contact map predictor that uses SVMs and a large set of informative features. SVMcon yields good performance on medium- to long-range contact predictions and can be modularly incorporated into a structure prediction pipeline.
- Full Text
- View/download PDF
29. Evolution of a Bifunctional Enzyme: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
- Author
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Bazan, J. Fernando, Fletterick, Robert J., and Pilkis, Simon J.
- Published
- 1989
30. Optimal Protein-Folding Codes from Spin-Glass Theory
- Author
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Goldstein, Richard A., Luthey-Schulten, Zaida A., and Wolynes, Peter G.
- Published
- 1992
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