1. Theoretical characterization of the shikimate 5-dehydrogenase reaction from Mycobacterium tuberculosis by hybrid QC/MM simulations and quantum chemical descriptors
- Author
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José Fernando Ruggiero Bachega, Martin J. Field, Gerd B. Rocha, Luis Fernando Saraiva Macedo Timmers, Rafael Andrade Caceres, Igor Barden Grillo, Osmar Norberto de Souza, Departamento de Química, Centro de Ciências Exatas e da Natureza Universidade Federal da Paraíba, Departamento de Farmacociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Centro de Biotecnologia da Universidade Federal do Rio Grande do Sul (CBiot/UFRGS), Programa de Pós-graduação em Biologia Celular e Molecular (PPGBCM), Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas (LABIO), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Programa de Pós-Graduação em Biotecnologia (PPGBiotec), Universidade do Vale do Taquari - Univates, Programa de Pós-Graduação em Biologia Celular e Molecular, Groupe modélisation et chimie théorique (MCT ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Theory Group, Institut Laue-Langevin, Universidade Federal da Paraiba (UFPB), Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Universidade do Vale do Taquari (UNIVATES), Pontifical Catholic University of Rio Grande do Sul (PUC-RS), and Institut Laue-Langevin (ILL)
- Subjects
Reaction mechanism ,Proton ,Dehydrogenase ,Shikimate 5-dehydrogenase ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Catalysis ,Substrate Specificity ,Inorganic Chemistry ,Mycobacterium tuberculosis ,Molecular dynamics ,Residue (chemistry) ,molecular mechanical potentials ,Computational chemistry ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,0103 physical sciences ,Fast quantum chemical descriptors ,Physical and Theoretical Chemistry ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Free-energy profiles ,010304 chemical physics ,biology ,Chemistry ,Hydride ,Organic Chemistry ,Active site ,biology.organism_classification ,[INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,3. Good health ,0104 chemical sciences ,Computer Science Applications ,Alcohol Oxidoreductases ,Computational Theory and Mathematics ,biology.protein ,Biocatalysis ,Quantum Theory ,Quantum chemical ,[CHIM.CHEM]Chemical Sciences/Cheminformatics - Abstract
International audience; In this study, we have investigated the enzyme shikimate 5-dehydrogenase from the causative agent of tuberculosis,Mycobacterium tuberculosis. We have employed a mixture of computational techniques, including molecular dynamics, hybrid quantum chemical/molecular mechanical potentials, relaxed surface scans, quantum chemical descriptors and free-energy simulations, to elucidate the enzyme's reaction pathway. Overall, we find a two-step mechanism, with a single transition state, that proceeds by an energetically uphill hydride transfer, followed by an energetically downhill proton transfer. Our mechanism and calculated free energy barrier for the reaction, 64.9 kJ mol(- 1), are in good agreement with those predicted from experiment. An analysis of quantum chemical descriptors along the reaction pathway indicated a possibly important, yet currently unreported, role of the active site threonine residue, Thr65.
- Published
- 2020
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