Basner Jodi E, Schwartz Steven D
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
J Am Chem Soc. 2005 Oct 12;127(40):13822-31. doi: 10.1021/ja043320h.
We have applied the Transition Path Sampling algorithm to the reaction catalyzed by the enzyme Lactate Dehydrogenase. This study demonstrates the ease of scaling Transition Path Sampling for applications on many degree of freedom systems, whose energy surface is a complex terrain of valleys and saddle points. As a Monte Carlo importance sampling method, transition path sampling is capable of surmounting barriers in path phase space and focuses simulation on the rare event of enzyme catalyzed atom transfers. Generation of the transition path ensemble, for this reaction, resolves a paradox in the literature in which some studies exposed the catalytic mechanism of hydride and proton transfer by lactate dehydrogenase to be concerted and others stepwise. Transition path sampling has confirmed both mechanisms as possible paths from reactants to products. With the objective to identify a generalized, reduced reaction coordinate, time series of both donor-acceptor distances and residue distances from the active site have been examined. During the transition from pyruvate to lactate, residues located behind the transferring hydride collectively compress toward the active site causing residues located behind the hydride acceptor to relax away. It is demonstrated that an incomplete compression/relaxation transition across the donor-acceptor axis compromises the reaction.
我们已将过渡路径采样算法应用于由乳酸脱氢酶催化的反应。这项研究表明，过渡路径采样易于扩展，可应用于多自由度系统，其能量表面是由山谷和鞍点构成的复杂地形。作为一种蒙特卡罗重要性采样方法，过渡路径采样能够跨越路径相空间中的障碍，并将模拟重点放在酶催化原子转移的罕见事件上。对于该反应，过渡路径系综的生成解决了文献中的一个悖论，其中一些研究表明乳酸脱氢酶催化的氢化物和质子转移的催化机制是协同的，而另一些研究则认为是分步的。过渡路径采样已证实这两种机制都是从反应物到产物的可能路径。为了确定一个广义的、简化的反应坐标，我们研究了供体 - 受体距离和与活性位点的残基距离的时间序列。在从丙酮酸向乳酸的转变过程中，位于转移氢化物后方的残基会集体向活性位点压缩，导致位于氢化物受体后方的残基松弛。结果表明，横跨供体 - 受体轴的不完全压缩/松弛转变会损害反应。
