酶催化过程的量子-经典力学研究进展  

QM/MM study of the enzymatic catalysis

作　　者：樊芳芳 付玉状 曹泽星[2] Fangfang Fan;Yuzhuang Fu;Zexing Cao(School of Biological and Chemical Engineering,Zhejiang University of Science and Technology,Hangzhou 310023,China;State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry,College of Chemistry and Chemical Engineering,Xiamen University,Xiamen 361005,China)

机构地区：[1]浙江科技学院生物与化学工程学院,杭州310023 [2]厦门大学化学化工学院,固体表面物理化学国家重点实验室,福建省理论与计算化学重点实验室,厦门361005

出　　处：《科学通报》2021年第10期1131-1143,共13页Chinese Science Bulletin

基　　金：国家自然科学基金(21873078,21673185,21933009)资助。

摘　　要：酶催化主要包括底物输运及其与活性位的结合、蛋白质限域环境中的化学反应以及产物释放等复杂的物理和化学过程,其中任一化学和非化学步都有可能决定酶的活性.通过量子/分子力学组合方法(QM/MM)计算和分子动力学模拟(MD),结合伞形采样,可以揭示酶催化过程的微观机理和底物输运的通道机制,分析底物进出口袋过程的热力学和动力学性质,探明整个酶催化过程中的决速步骤以及关键残基的作用.本文概述了近几年对几类生物体系量子-经典力学模拟研究的进展,并对QM/MM多尺度模拟方法的发展进行了展望.Enzyme catalysis generally includes multiple physical and chemical processes,such as the substrate transportion and binding to the active site,the chemical reaction in the protein confined environment,and the product release,where any chemical or nonchemical step is probably to dominate the activity of enzyme.In order to understand the enzymatic efficiency,the classical molecular dynamics(MM MD)and combined quantum and classical molecular dynamics(QM/MM MD)simulations,in combination with the umbrella sampling,have been used to explore mechanisms for the enzymatic catalysis and the substrate transportion in several biological systems,including the detoxification of the G-type nerve agent sarin by phosphotriesterase(PTE),the hydrolysis of uridine by the pyrimidine-specific nucleoside hydrolase Yeik(CU-NH),and the transportation of naphthalimide-polyamine compounds into the drug sites by the bovine serum albumin(BSA).Extensive QM/MM MD and MM MD simulations show that the wild-type PTE enzyme is capable of hydrolyzing sarin but with a low catalytic efficiency.Dissociation of the degraded product from the binuclear zinc center is predicted to be the rate-determining step with the free-energy barrier of 21.0 kcal/mol,and the multiple chemical steps are involved in the dissociation process.The P-F cleavage of the substrate sarin follows a two-step mechanism,in which the nucleophilic attack of the bridging hydroxide leads to the P-O_(μ)formation with the free-energy barrier of 9.8 kcal/mol,and the subsequent P-F cleavage and the proton transfer from theμ-OH to the residue Asp301 yields the degraded product with the free-energy span of 12.3 kcal/mol.The relatively strong hydrogen-bond interactions between the substrate uridine and key residues in the active site of CU-NH play an important role in the substrate specificity.The enzymatic N-glycosidic bond cleavage of uridine by CU-NH is the rate-limiting step with the free energy barrier of about 20 kcal/mol,and the substrate protonation less influences the activity of CU

关 键 词：磷酸三酯酶 核苷水解酶 酶催化 QM/MM和MM MD模拟 

分 类 号：Q814[生物学—生物工程]