Theoretical characterization of the shikimate 5-dehydrogenase reaction fromMycobacterium tuberculosisby hybrid QC/MM simulations and quantum chemical descriptors

Igor Barden Grillo (1) , José Fernando Ruggiero Bachega (2) , Luís Fernando S. M. Timmers (3) , Rafael A. Caceres (2) , Osmar Norberto de Souza (4) , Martin J. Field (5, 6) , Gerd Bruno Rocha (1)

1 UFPB - Universidade Federal da Paraiba / Federal University of Paraiba
2 UFCSPA - Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre
3 UNIVATES - Universidade do Vale do Taquari
4 PUC-RS - Pontifícia Universidade Católica do Rio Grande do Sul [Brasil] = Pontifical Catholic University of Rio Grande do Sul [Brazil] = Université catholique pontificale de Rio Grande do Sul [Brésil]
5 MCT - Groupe modélisation et chimie théorique
6 ILL - Institut Laue-Langevin

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.

Mots clés: Mycobacterium tuberculosis; Free-energy profiles; Fast quantum chemical descriptors; Quantum chemical; molecular mechanical potentials; Reaction mechanism; Shikimate 5-dehydrogenase

Domaines: Biochimie [q-bio.BM]; Chemo-informatique; Bactériologie

Igor Barden Grillo, José Fernando Ruggiero Bachega, Luís Fernando S. M. Timmers, Rafael A. Caceres, Osmar Norberto de Souza, et al.. Theoretical characterization of the shikimate 5-dehydrogenase reaction fromMycobacterium tuberculosisby hybrid QC/MM simulations and quantum chemical descriptors. Journal of Molecular Modeling, 2020, 26 (11), pp.297. ⟨10.1007/s00894-020-04536-9⟩. ⟨hal-02987221⟩