Theoretical characterization of the shikimate 5-dehydrogenase reaction from Mycobacterium tuberculosis by hybrid QC/MM s
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ORIGINAL PAPER
Theoretical characterization of the shikimate 5-dehydrogenase reaction from Mycobacterium tuberculosis by hybrid QC/MM simulations and quantum chemical descriptors Igor Barden Grillo1 · Jose´ Fernando Ruggiero Bachega2,3,4 · Luis Fernando S. M. Timmers2,5 · Rafael A. Caceres6 · Osmar Norberto de Souza2,7 · Martin J. Field8,9 · Gerd Bruno Rocha1 Received: 2 June 2020 / Accepted: 7 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 freeenergy 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. Keywords Mycobacterium tuberculosis · Free-energy profiles · Fast quantum chemical descriptors · Quantum chemical/molecular mechanical potentials · Reaction mechanism · Shikimate 5-dehydrogenase
Introduction Enzymes are the most important catalysts in life chemistry. These proteins can increase reaction rates by a factor up to 1019 , thereby tuning the chemical reactions in metabolic pathways [42]. As a result, enzymes have substantial relevance in many areas of biochemistry, including biotechnology, nanoscience, and medicinal chemistry. The selection of a suitable protein to target is a crucial step in the drug development process of bioactive molecules, such as drugs and herbicides. The protein should either be in the
This paper belongs to Topical Collection XX-Brazilian Symposium of Theoretical Chemistry (SBQT2019) Igor Barden Grillo and Jos´e Fernando Ruggiero Bachega are co-first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-020-04536-9) contains supplementary material, which is available to authorized users. Igor Barden Grillo
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metabolic pathway that is present in the pathogen but absent in the hosts, following the rule of selective toxicity, or be sufficiently different that it can be specifically targeted. The shikimate (SKM) pathway [19] is a seven-step enzymatic pathway that converts erythrose 4-phosphate and phosphoenolpyruvate to chorismate, a biosynthetic precursor of aromatic amino acids, vitamins B9 and K1, ubiquinone, and salicylate. This route is present in plants
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