Departamento de Química, Centro de Ciências Exatas e da Natureza Universidade Federal da Paraíba, João Pessoa, Brazil.
Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas (LABIO), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) Programa de Pós-Graduação em Biologia Celular e Molecular, Av. Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil.
J Mol Model. 2020 Oct 8;26(11):297. doi: 10.1007/s00894-020-04536-9.
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, 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.
在这项研究中，我们研究了结核分枝杆菌（导致结核病的病原体）中的酶莽草酸 5-脱氢酶。我们采用了多种计算技术，包括分子动力学、混合量子化学/分子力学势、弛豫表面扫描、量子化学描述符和自由能模拟，以阐明该酶的反应途径。总的来说，我们发现了一种两步机制，其中只有一个过渡态，通过能量上坡的氢转移进行，然后是能量下坡的质子转移。我们的反应机制和计算得到的自由能势垒为 64.9kJ/mol，与实验预测的结果非常吻合。对反应途径中量子化学描述符的分析表明，活性位点苏氨酸残基 Thr65 可能起着重要作用，但目前尚未报道。
