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15 results on '"National Institute for Health and Medical Research (INSERM), France"'

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

Author

Narayanaswamy Srinivasan, Bernard Offmann, Iyanar Vetrivel, Frédéric Cadet, Alexandre G. de Brevern, de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), PEACCEL, Molecular Biophysics Unit, Indian Institute of Science, Région Réunion and the Fond Social Européen, Conseil Regional des Pays de la Loire in the framework of GRIOTE project, the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne, Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Université de La Réunion, Faculty of Sciences and Technology, Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2), Department of Biotechnology, Government of India, J.C. Bose National Fellow, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, Structural alphabet, [SDV]Life Sciences [q-bio], Datasets as Topic, Molecular Dynamics Simulation, Molecular dynamics, Biochemistry, Mice, 03 medical and health sciences, Protein structural variation, Protein structure, Protein Domains, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Databases, Protein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Bacteria, 030102 biochemistry & molecular biology, Chemistry, Proteins, General Medicine, Protein superfamily, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Nmr data, [SDV] Life Sciences [q-bio], 030104 developmental biology, Protein conformation, Structural Homology, Protein, Structural plasticity, Biophysics
Abstract

International audience; Understanding the structural plasticity of proteins is key to understanding the intricacies of their functions and mechanistic basis. In the current study, we analyzed the available multiple crystal structures of the same protein for the structural differences. For this purpose we used an abstraction of protein structures referred as Protein Blocks (PBs) that was previously established. We also characterized the nature of the structural variations for a few proteins using molecular dynamics simulations. In both the cases, the structural variations were summarized in the form of substitution matrices of PBs. We show that certain conformational states are preferably replaced by other specific conformational states. Interestingly, these structural variations are highly similar to those previously observed across structures of homologous proteins (r 2 =0.923) or across the ensemble of conformations from NMR data (r 2 =0.919). Thus our study quantitatively shows that overall trends of structural changes in a given protein are nearly identical to the trends of structural differences that occur in the topologically equivalent positions in homologous proteins. Specific case studies are used to illustrate the nature of these structural variations.

Published
2019
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3. Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Author

Alexandre G. de Brevern, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ministry of Research (France)., University of Paris, University Paris Diderot, Sorbonne Paris Cité (France)., French National Computing Centre CINES under grant no. A0070710961 by the GENCI (Grand Equipement National de Calcul Intensif)., Conseil Régional Ile de France. INTS (SESAME Grant)., University of La Réunion, Réunion Island (France)., National Institute for Health and Medical Research (INSERM, France)., National Institute for Blood Transfusion (INTS, France)., Indo-French Centre for the Promotion of Advanced Research/CEFIPRA: 5302-2., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
protein blocks, Protein Conformation, Computer science, Entropy, lcsh:QR1-502, Rigidity (psychology), Molecular Dynamics Simulation, Biochemistry, lcsh:Microbiology, 03 medical and health sciences, Molecular dynamics, intrinsic disorder regions, Protein structure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Statistical physics, Databases, Protein, Molecular Biology, 030304 developmental biology, Flexibility (engineering), 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Continuum (topology), Communication, protein flexibility, 030302 biochemistry & molecular biology, Atom (order theory), intrinsic disorder proteins, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mobility, molecular dynamics, Characterization (materials science), Intrinsically Disordered Proteins, nuclear magnetic resonance, Order (biology), protein structures, alpha-Synuclein, X-ray structures
Abstract

International audience; Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.

Published
2020
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4. Discrete analyses of protein dynamics

Author

Vattekatte, Akhila Melarkode, Narwani, Tarun, Craveur, Pierrick, Shinada, Nicolas, Floch, Aline, Santuz, Hubert, Melarkode Vattekatte, Akhila, Srinivasan, Narayanaswamy, Rebehmed, Joseph, Gelly, Jean-Christophe, Etchebest, Catherine, De Brevern, Alexandre, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Scripps Research Institute, Discngine S.A.S [Paris], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Molecular Biophysics Unit, Indian Institute of Science, Department of Computer Science and Mathematics [Lebanese American University] (CSM/SAS/LAU), Lebanese American University (LAU), the Ministry of Research (France), University de Paris, University Paris Diderot, Sorbonne Paris Cité (France), National Institute for Blood Transfusion (INTS, France), National Institute for Health and Medical Research (INSERM, France), Indo-French Centre for the Promotion of Advanced Research / CEFIPRA for collaborative grant (number 5302-2)., Allocation de Recherche Réunion granted by the Conseil Régional de la Réunion and the European Social Fund EU (ESF), ANRT, French National Computing Centre CINES under grant no. A0010707621 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. c2013037147 by the GENCI (Grand Equipement National de Calcul Intensif)., French National Computing Centre CINES under grant no. A0040710426 by the GENCI (Grand Equipement National de Calcul Intensif)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-10-CD2I-0014,NaturaDyRe,Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs(2010), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Scripps Research Institute [La Jolla, San Diego], de Brevern, Alexandre G., Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, and Chimie Durable – Industries – Innovation - Réactions d'oxydation biocatalysées efficaces pour la synthèse de composés naturels ou énantiopurs - - NaturaDyRe2010 - ANR-10-CD2I-0014 - CD2I - VALID

Subjects
solvent accessibility, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Protein Conformation, Entropy, Protein Data Bank (RCSB PDB), Molecular Dynamics Simulation, Protein Structure, Secondary, 03 medical and health sciences, Molecular dynamics, Protein structure, Protein DataBank, Structural Biology, Simple (abstract algebra), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Statistical physics, Molecular Biology, Protein secondary structure, 030304 developmental biology, Physics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Entropy (statistical thermodynamics), Protein dynamics, 030302 biochemistry & molecular biology, Proteins, secondary structure, General Medicine, disorder, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], molecular dynamics, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, flexibility, structural alphabet, Macromolecule, local protein conformations
Abstract

Protein structures are highly dynamic macromolecules. This dynamics is often analysed through experimental and/or computational methods only for an isolated or a limited number of proteins. Here, we explore large-scale protein dynamics simulation to observe dynamics of local protein conformations using different perspectives. We analysed molecular dynamics to investigate protein flexibility locally, using classical approaches such as RMSf, solvent accessibility, but also innovative approaches such as local entropy. First, we focussed on classical secondary structures and analysed specifically how β-strand, β-turns, and bends evolve during molecular simulations. We underlined interesting specific bias between β-turns and bends, which are considered as the same category, while their dynamics show differences. Second, we used a structural alphabet that is able to approximate every part of the protein structures conformations, namely protein blocks (PBs) to analyse (i) how each initial local protein conformations evolve during dynamics and (ii) if some exchange can exist among these PBs. Interestingly, the results are largely complex than simple regular/rigid and coil/flexible exchange. AbbreviationsNeqnumber of equivalentPBProtein BlocksPDBProtein DataBankRMSfroot mean square fluctuationsCommunicated by Ramaswamy H. Sarma.

Published
2019
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5. 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
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6. 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
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7. 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
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8. 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
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9. Bioinformatic analysis of the protein/DNA interface

Author

Daniel Svozil, Jiří Černý, Bohdan Schneider, Alexandre G. de Brevern, Agnel Praveen Joseph, Jean-Christophe Gelly, de Brevern, Alexandre G., Institute of Biotechnology AS CR, Laboratory of Informatics and Chemistry, Institute of Chemical Technology [Prague] (ICT), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Czech-France collaboration Barrande [MEB021032], BIOCEV CZ.1.05/1.1.00/02.0109 from the ERDF, [P305/ 80 12/1801] from the Czech Science Foundation, and institutional [AV0Z50520701], supported by [MSM 6046137302 to D.S. and P.Č.], and supported by the Ministry of Research (France), University Paris Diderot, Sorbonne Paris Cité (France), National Institute of Blood Transfusion (INTS, France), National Institute of Health and Medical Research (INSERM, France) and 'Investissements d'avenir', Laboratories of Excellence GR-Ex (France) (to J.C.G. and A.G.dB.). Funding for open access charge: Czech Science Foundation and Academy of Sciences of the Czech Republic.

Subjects
Models, Molecular, Protein Conformation, DNA interface, Crystal structure, Plasma protein binding, Pentapeptide repeat, chemistry.chemical_compound, 0302 clinical medicine, structural alphabet: Protein Blocks, MESH: Protein Conformation, Protein structure, Structural Biology, Structural motif, Conformational isomerism, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: DNA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], DNA-Binding Proteins, MESH: Nucleic Acid Conformation, Naked DNA, Data Interpretation, Statistical, MESH: Phosphates, MESH: Models, Molecular, Protein Binding, MESH: Computational Biology, Stereochemistry, Biophysics, Biology, DNA-binding protein, Phosphates, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Water, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Transcription factor, 030304 developmental biology, Computational Biology, Water, DNA structure, DNA, Base (topology), Crystallography, chemistry, protein structures, Nucleic acid, Nucleic Acid Conformation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], DNA interactions, protein, MESH: Data Interpretation, Statistical, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract

Despite extensive studies of the geometry of protein/DNA interfaces the understanding of the affinity and specificity of the protein/DNA interactions remains elusive. We present a novel approach to geometric analysis of protein/nucleic acid interfaces that is based on classification of their local conformations. Protein structures are divided into a series of pentapeptide fragments and each is assigned one of 16 conformers or ‘protein blocks’ [de Brevern et al. Proteins 41, 271 (2000)]. Similarly, each DNA step (unit [base]sugar-phosphate-sugar[base]) is assigned one of ∼20 DNA conformers [Svozil et al. NAR 36, 3690 (2008)]. Significantly, local structures classified into distinct conformers can be represented by symbols so that they can be analyzed more easily than complicated 3D objects. Size of the fragments used for the classification allows analysis of structural features of the interface at a scale intermediate between too detailed interatomic contacts on one side and too crude protein motifs (helix-turn-helix, Zn-finger, ...) on the other. We will present correlations between protein and DNA conformers at their interface from more than 15 hundred protein/DNA crystal structures broken by various criteria of the analyzed structures as protein functional classification, e.g. in GO or Pfam or by crystallographic properties, resolution or overall structure quality.Acknowledgments. This work was supported by Czech-France collaboration Barrande (MEB021032) and Czech Science Foundation (P305/10/2184).

Published
2013
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10. β-Bulges: extensive structural analyses of β-sheets irregularities

Author

Craveur, Pierrick, Joseph, Agnel Praveen, Rebehmed, Joseph, De Brevern, Alexandre, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), The Ministry of Research (France), The University Paris Diderot, Sorbonne Paris Cite (France), The National Institute of Blood Transfusion (INTS, France), The National Institute of Health and Medical Research (INSERM, France), The Laboratories of Excellence, GR-Ex (France), HFSP (India), NCBS (India), and de Brevern, Alexandre G.

Subjects
[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Conformation, Molecular Sequence Data, Proteins, Hydrogen Bonding, Articles, bioinformatics, Molecular Dynamics Simulation, sequence, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Protein Structure, Secondary, protein aggregation, Evolution, Molecular, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Amino Acids, protein structure, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], structure relationship, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

International audience; β-Sheets are quite frequent in protein structures and are stabilized by regular main-chain hydrogen bond patterns. Irregularities in β-sheets, named β-bulges, are distorted regions between two consecutive hydrogen bonds. They disrupt the classical alternation of side chain direction and can alter the directionality of β-strands. They are implicated in protein-protein interactions and are introduced to avoid β-strand aggregation. Five different types of β-bulges are defined. Previous studies on β-bulges were performed on a limited number of protein structures or one specific family. These studies evoked a potential conservation during evolution. In this work, we analyze the β-bulge distribution and conservation in terms of local backbone conformations and amino acid composition. Our dataset consists of 66 times more β-bulges than the last systematic study (Chan et al. Protein Science 1993, 2:1574-1590). Novel amino acid preferences are underlined and local structure conformations are highlighted by the use of a structural alphabet. We observed that β-bulges are preferably localized at the N- and C-termini of β-strands, but contrary to the earlier studies, no significant conservation of β-bulges was observed among structural homologues. Displacement of β-bulges along the sequence was also investigated by Molecular Dynamics simulations.

Published
2013
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11. Evolution study of the Baeyer-Villiger monooxygenases enzyme family: functional importance of the highly conserved residues

Author

Véronique de Berardinis, Véronique Alphand, Alexandre G. de Brevern, Joseph Rebehmed, GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The National Center for Atomic Research (CEA,France) University d'Aix-Marseille (France) The National Center for Scientific Research (CNRS,France) high performance computing (HPC) resources at the French National Computing Center CINES under grant no. 2012-c2012076930 funded by the GENCI (Grand Equipement National de Calcul Intensif)., Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and de Brevern, Alexandre G.

Subjects
Threonine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, ketones, phylogeny, 01 natural sciences, Biochemistry, Conserved sequence, Mixed Function Oxygenases, Protein structure, esters, Rhodococcus, [INFO.INFO-BT]Computer Science [cs]/Biotechnology, lactones, Conserved Sequence, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], chemistry.chemical_classification, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, enentioselectivity, [CHIM.CATA] Chemical Sciences/Catalysis, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Amino acid, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, sequence alignment, Flavin-Adenine Dinucleotide, Stereochemistry, Sequence alignment, Biology, 010402 general chemistry, stereoselectivity, 03 medical and health sciences, Pseudomonas, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein structure, 030304 developmental biology, function, Binding Sites, [CHIM.CATA]Chemical Sciences/Catalysis, Monooxygenase, interactions, [CHIM.ORGA] Chemical Sciences/Organic chemistry, 0104 chemical sciences, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Enzyme binding, [INFO.INFO-BT] Computer Science [cs]/Biotechnology, chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Function (biology), NADP
Abstract

International audience; Baeyer-Villiger monooxygenases (BVMOs) catalyze the transformation of linear and cyclic ketones into their corresponding esters and lactones by introducing an oxygen atom into a C-C bond. This bioreaction has numerous advantages compared to its chemical version; it does not induce the use of potentially harmful reagents (i.e., green chemistry) and displays significant better enantio- and regio-selectivity. New potential BVMOs were searched using sequence homology for type I BVMO proteins. 116 new sequences were identified as new putative BVMOs respecting the defined selection criteria. Multiple sequence alignments were carried out on the selected sequences to study the conservation of structurally and/or functionally important amino acids during evolution. Type I BVMO signature motif was found to be conserved in 94.8% of the sequences. We noticed also the highly conserved - but previously unnoticed - Threonine 167 (93.1%), located in the signature motif; this position could be added in the pattern used to characterize specific Type I enzymes. Amino acids at the vicinity of the FAD and NADPH cofactors were found also to be highly conserved and the details of the interactions were emphasized. Interestingly, residues at the enzyme binding site were found less conserved in terms of sequence evolution, leading sometimes to some important amino acid changes. These behaviors could explain the enzyme selectivity and specificity for different ligands.

Published
2013
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12. VLDP web server: a powerful geometric tool for analysing protein structures in their environment

Author

Alexandre G. de Brevern, Jeremy Esque, Sylvain Leonard, Christophe Oguey, Laboratoire de Physique Théorique et Modélisation (LPTM - UMR 8089), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The University of Cergy-Pontoise (France) The National Center for Scientific Research (CNRS,France), de Brevern, Alexandre G., and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)

Subjects
Models, Molecular, Web server, MESH: Amino Acids, Protein Conformation, Voronoi, protein accessibility, Biology, Bioinformatics, computer.software_genre, 01 natural sciences, tessellations, Set (abstract data type), 03 medical and health sciences, MESH: Software, Protein structure, MESH: Protein Conformation, 0103 physical sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, Delaunay, Internet, 0303 health sciences, amino acids, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tessellation, 010304 chemical physics, Delaunay triangulation, Proteins, Articles, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Visualization, MESH: Internet, protein structures, Laguerre polynomials, protein volume, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Voronoi diagram, computer, Algorithm, Software, MESH: Models, Molecular
Abstract

International audience; Protein structures are an ensemble of atoms determined experimentally mostly by X-ray crystallography or Nuclear Magnetic Resonance. Studying 3D protein structures is a key point for better understanding protein function at a molecular level. We propose a set of accurate tools, for analysing protein structures, based on the reliable method of Voronoi-Laguerre tessellations. The Voronoi Laguerre Delaunay Protein web server (VLDPws) computes the Laguerre tessellation on a whole given system first embedded in solvent. Through this fine description, VLDPws gives the following data: (i) Amino acid volumes evaluated with high precision, as confirmed by good correlations with experimental data. (ii) A novel definition of inter-residue contacts within the given protein. (iii) A measure of the residue exposure to solvent that significantly improves the standard notion of accessibility in some cases. At present, no equivalent web server is available. VLDPws provides output in two complementary forms: direct visualization of the Laguerre tessellation, mostly its polygonal molecular surfaces; files of volumes; and areas, contacts and similar data for each residue and each atom. These files are available for download for further analysis. VLDPws can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/vldp.

Published
2013
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13. Cis-trans isomerization of omega dihedrals in proteins

Author

Pierrick Craveur, Pierre Poulain, Joseph Rebehmed, Agnel Praveen Joseph, Alexandre G. de Brevern, de Brevern, Alexandre G., GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) HFSP (India), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, cis-trans-Isomerases, Protein Folding, Stereochemistry, Protein Conformation, MESH: Protein Folding, Clinical Biochemistry, Dihedral angle, Molecular Dynamics Simulation, 010402 general chemistry, Crystallography, X-Ray, 01 natural sciences, Biochemistry, iPBA, 03 medical and health sciences, Molecular dynamics, Protein structure, MESH: Protein Conformation, MESH: Protein Stability, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Peptide bond, Humans, MESH: Molecular Dynamics Simulation, MESH: Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protein superimposition, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], MESH: Humans, Chemistry, Protein Stability, Organic Chemistry, Proteins, Protein structure prediction, protein function, MESH: Crystallography, X-Ray, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cis trans isomerization, 0104 chemical sciences, protein structures, Protein folding, structural alphabet, isomerisation, MESH: cis-trans-Isomerases, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Isomerization, MESH: Models, Molecular
Abstract

International audience; Peptide bonds in protein structures are mainly found in trans conformation with a torsion angle ω close to 180°. Only a very low proportion is observed in cis conformation with ω angle around 0°. Cis-trans isomerization leads to local conformation changes which play an important role in many biological processes. In this paper, we reviewed the recent discoveries and research achievements in this field. First, we presented some interesting cases of biological processes in which cis-trans isomerization is directly implicated. It is involved in protein folding and various aspect of protein function like dimerization interfaces, autoinhibition control, channel gating, membrane binding. Then we reviewed conservation studies of cis peptide bonds which emphasized evolution constraints in term of sequence and local conformation. Finally we made an overview of the numerous molecular dynamics studies and prediction methodologies already developed to take into account this structural feature in the research area of protein modeling. Many cis peptide bonds have not been recognized as such due to the limited resolution of the data and to the refinement protocol used. Cis-trans proline isomerization reactions represents a vast and promising research area that still needs to be further explored for a better understanding of isomerization mechanism and improvement of cis peptide bond predictions.

Published
2013
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14. DoSA: Database of Structural Alignments

Author

Alexandre G. de Brevern, Bernard Offmann, Garima Agarwal, Narayanaswamy Srinivasan, Mohammed Iftekhar, Swapnil Mahajan, Dynamique des Structures et Interactions des Macromolécules Biologiques - Pôle de La Réunion (DSIMB Réunion), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Molecular Biophysics Unit, Indian Institute of Science, GR-Ex, Laboratoire d'Excellence, GR-Ex, National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), MBU, Indian Institute of Science-Indian Institute of Science, Indo-French collaborative grant (CEFIPRA/IFCPAR 3903-E) The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France) The University of Nantes (France) Fonds Européen de Dévelopment Régional and Conseil Regional de La Réunion [20100079, Tiers: 144645] Department of Biotechnology (India), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), and de Brevern, Alexandre G.

Subjects
Models, Molecular, PALI, substitution matrix, optimisation, Statistics as Topic, MESH: Amino Acid Sequence, Molecular Biophysics Unit, computer.software_genre, Protein structure, MESH: Proteins, Databases, Protein, Structural motif, database, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Structural Homology, Protein, 0303 health sciences, Protein function, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Database, 030302 biochemistry & molecular biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], CLUSTALW, Original Article, Structural alphabet, General Agricultural and Biological Sciences, MESH: Models, Molecular, Information Systems, MESH: Databases, Protein, Molecular Sequence Data, Biology, iPBA, General Biochemistry, Genetics and Molecular Biology, Substitution matrix, Access to Information, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, protein structure, Spatial Orientations, MESH: Statistics as Topic, 030304 developmental biology, MESH: Molecular Sequence Data, Proteins, Protein superfamily, MESH: Access to Information, Functional integrity, Structural Homology, Protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], protein structure superimposition, computer
Abstract

International audience; Protein structure alignment is a crucial step in protein structure-function analysis. Despite the advances in protein structure alignment algorithms, some of the local conformationally similar regions are mislabeled as structurally variable regions (SVRs). These regions are not well superimposed because of differences in their spatial orientations. The Database of Structural Alignments (DoSA) addresses this gap in identification of local structural similarities obscured in global protein structural alignments by realigning SVRs using an algorithm based on protein blocks. A set of protein blocks is a structural alphabet that abstracts protein structures into 16 unique local structural motifs. DoSA provides unique information about 159,780 conformationally similar and 56,140 conformationally dissimilar SVRs in 74 705 pairwise structural alignments of homologous proteins. The information provided on conformationally similar and dissimilar SVRs can be helpful to model loop regions. It is also conceivable that conformationally similar SVRs with conserved residues could potentially contribute toward functional integrity of homologues, and hence identifying such SVRs could be helpful in understanding the structural basis of protein function. Database URL: http://bo-protscience.fr/dosa/

Published
2013
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15. Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the β3 Subunit of the αIIbβ3 Integrin

Author

Alexandre G. de Brevern, Pierre Poulain, Vincent Jallu, Patrick F.J. Fuchs, Cécile Kaplan, Laboratoire d'immunologie plaquettaire, Institut National de la Transfusion Sanguine [Paris] (INTS), GR-Ex, Laboratoire d'Excellence, GR-Ex, Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Ministry of Research (France) The University Paris Diderot, Sorbonne Paris Cite (France) The National Institute of Blood Transfusion (INTS, France) The National Institute of Health and Medical Research (INSERM, France) The Laboratories of Excellence, GR-Ex (France), de Brevern, Alexandre G., and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 030204 cardiovascular system & hematology, Molecular Dynamics, Epitope, MESH: Genotype, Epitopes, Computational Chemistry, 0302 clinical medicine, Protein structure, Genotype, MESH: Molecular Dynamics Simulation, Platelet, MESH: Models, Genetic, Immune Response, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Antigens, Human Platelet, Genetics, variants, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Integrin beta3, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Immunizations, MESH: Platelet Glycoprotein GPIIb-IIIa Complex, alloimmunisation, Platelet Glycoprotein GPIIb-IIIa Complex, Chemistry, Medicine, Research Article, Platelets, endocrine system, MESH: Epitopes, Science, Immunology, Integrin, Molecular Dynamics Simulation, Biology, 03 medical and health sciences, Antigen, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antigens, Human Platelet, Allele, Alleles, 030304 developmental biology, Evolutionary Biology, MESH: Humans, Polymorphism, Genetic, Population Biology, Models, Genetic, Transfusion Medicine, MESH: Alleles, Immunity, Computational Biology, Thrombocytopenia, protein structures, Genetic Polymorphism, biology.protein, Clinical Immunology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Population Genetics
Abstract

International audience; BACKGROUND: The HPA-1 alloimmune system carried by the platelet integrin αIIbβ3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the β3 subunit. Although the structure of αIIbβ3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions. METHODOLOGY/PRINCIPAL FINDINGS: A complete 3D model of the L33-β3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 β3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 β3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains. CONCLUSIONS: These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the β3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and β3 structure that suggest possible effects on the alloimmune response and platelet function.

Published
2012
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