Theoretical characterization of the shikimate 5-dehydrogenase reaction from Mycobacterium tuberculosis by hybrid QC/MM simulations and quantum chemical descriptors

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.