Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
J Chem Theory Comput. 2016 Apr 12;12(4):2047-54. doi: 10.1021/acs.jctc.5b01169. Epub 2016 Mar 14.
In this study, we develop and test a method to determine the rate of particle transfer and kinetic isotope effects in enzymatic reactions, specifically yeast alcohol dehydrogenase (YADH), from first-principles. Transition path sampling (TPS) and normal mode centroid dynamics (CMD) are used to simulate these enzymatic reactions without knowledge of their reaction coordinates and with the inclusion of quantum effects, such as zero-point energy and tunneling, on the transferring particle. Though previous studies have used TPS to calculate reaction rate constants in various model and real systems, it has not been applied to a system as large as YADH. The calculated primary H/D kinetic isotope effect agrees with previously reported experimental results, within experimental error. The kinetic isotope effects calculated with this method correspond to the kinetic isotope effect of the transfer event itself. The results reported here show that the kinetic isotope effects calculated from first-principles, purely for barrier passage, can be used to predict experimental kinetic isotope effects in enzymatic systems.
在这项研究中，我们开发并测试了一种从第一性原理确定酶反应中粒子转移速率和动力学同位素效应的方法，特别是酵母醇脱氢酶（YADH）。过渡路径采样（TPS）和正则模态质心动力学（CMD）用于模拟这些酶反应，而无需了解其反应坐标，并包括转移粒子的零点能和隧道等量子效应。尽管先前的研究已经使用 TPS 在各种模型和实际系统中计算了反应速率常数，但它尚未应用于像 YADH 这样大的系统。计算得出的主要 H/D 动力学同位素效应与先前报道的实验结果在实验误差范围内一致。用这种方法计算的动力学同位素效应与转移事件本身的动力学同位素效应相对应。这里报道的结果表明，纯粹用于势垒穿越的第一性原理计算的动力学同位素效应可用于预测酶系统中的实验动力学同位素效应。
