Computation of kinetic isotope effects for enzymatic reactions  

作　　者：GAO JiaLi 

机构地区：[1]Department of Chemistry and Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA

出　　处：《中国科学：化学》2012年第1期112-112,共1页SCIENTIA SINICA Chimica

摘　　要：We describe a computational approach,incorporating quantum mechanics into enzyme kinetics modeling with a special emphasis on computation of kinetic isotope effects.Two aspects are highlighted:(1) the potential energy surface is represented by a combined quantum mechanical and molecular mechanical(QM/MM) potential in which the bond forming and breaking processes are modeled by electronic structure theory,and(2) a free energy perturbation method in path integral simulation is used to determine both kinetic isotope effects(KIEs).In this approach,which is called the PI-FEP/UM method,a light(heavy) isotope is mutated into a heavy(light) counterpart in centroid path integral simulations.The method is illustrated in the study of primary and secondary KIEs in two enzyme systems.In the case of nitroalkane oxidase,the enzymatic reaction exhibits enhanced quantum tunneling over that of the uncatalyzed process in water.In the dopa delarboxylase reaction,there appears to be distinguishable primary carbon-13 and secondary deuterium KIEs when the internal proton tautomerism is in the N-protonated or in the O-protonated positions.These examples show that the incorporation of quantum mechanical effects in enzyme kinetics modeling offers an opportunity to accurately and reliably model the mechanisms and free energies of enzymatic reactions.We describe a computational approach,incorporating quantum mechanics into enzyme kinetics modeling with a special emphasis on computation of kinetic isotope effects.Two aspects are highlighted：（1） the potential energy surface is represented by a combined quantum mechanical and molecular mechanical（QM/MM） potential in which the bond forming and breaking processes are modeled by electronic structure theory,and（2） a free energy perturbation method in path integral simulation is used to determine both kinetic isotope effects（KIEs）.In this approach,which is called the PI-FEP/UM method,a light（heavy） isotope is mutated into a heavy（light） counterpart in centroid path integral simulations.The method is illustrated in the study of primary and secondary KIEs in two enzyme systems.In the case of nitroalkane oxidase,the enzymatic reaction exhibits enhanced quantum tunneling over that of the uncatalyzed process in water.In the dopa delarboxylase reaction,there appears to be distinguishable primary carbon-13 and secondary deuterium KIEs when the internal proton tautomerism is in the N-protonated or in the O-protonated positions.These examples show that the incorporation of quantum mechanical effects in enzyme kinetics modeling offers an opportunity to accurately and reliably model the mechanisms and free energies of enzymatic reactions.

关 键 词：酶促反应动力学 同位素效应 计算动力学 量子力学效应 模拟电子 路径积分 动力学建模 动力学模型 

分 类 号：O511[理学—低温物理] X142[理学—物理]