Oanca Gabriel, Asadi Mojgan, Saha Arjun, Ramachandran Balajee, Warshel Arieh
Department of Chemistry, University of Southern California, Los Angeles, California 90089-1062, United States.
Structural Biology and Bio-computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu 630 004, India.
J Phys Chem B. 2020 Dec 17;124(50):11349-11356. doi: 10.1021/acs.jpcb.0c08192. Epub 2020 Dec 2.
Cysteine proteases play a major role in many life processes and are the target of key drugs. The reaction mechanism of these enzymes is a complex process, which involves several steps that are divided into two main groups: acylation and deacylation. In this work, we studied the energy profile for the acylation and a part of the deacylation reaction of three different enzymes, cruzain, papain, and the Q19A-mutated papain with the benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide (CBZ-FR-AMC) substrate. The calculations were performed using the EVB and PDLD/S-LRA methods. The overall agreement between the calculated and observed results is encouraging and indicates that we captured the correct reaction mechanism. Finally, our finding indicates that the minimum of the reaction profile, between the acylation and deacylation steps, should provide an excellent state for the binding of covalent inhibitors.
半胱氨酸蛋白酶在许多生命过程中发挥着重要作用，并且是关键药物的作用靶点。这些酶的反应机制是一个复杂的过程，它涉及几个步骤，这些步骤主要分为两组：酰化和脱酰化。在这项工作中，我们研究了三种不同的酶（克鲁兹蛋白酶、木瓜蛋白酶以及Q19A突变型木瓜蛋白酶）与苄氧羰基-苯丙氨酰精氨酸-4-甲基香豆素-7-酰胺（CBZ-FR-AMC）底物发生酰化反应以及部分脱酰化反应的能量分布。计算使用了EVB和PDLD/S-LRA方法。计算结果与观测结果总体上的一致性令人鼓舞，表明我们捕捉到了正确的反应机制。最后，我们的研究结果表明，在酰化和脱酰化步骤之间的反应分布最小值应为共价抑制剂的结合提供一个极佳的状态。
