Computer simulations of enzyme catalysis: finding out what has been optimized by evolution.
Computer simulations of enzyme catalysis: finding out what has been optimized by evolution.
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DOI：
10.1073/pnas.95.11.5950
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发表时间：
1998-05
影响因子：
11.1
通讯作者：
A. Warshel;J. Florián
中科院分区：
文献类型：
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作者：
A. Warshel;J. Florián
讨论了酶的催化能力的起源，注意到了进化的限制。指出酶催化反应所反映的能量贡献不能通过现有的实验方法来唯一确定，而不能通过计算机模拟研究来加强分析。能量考虑和计算机模拟的使用使得人们可以排除许多关于酶工作方式的流行提议。看来，有机化学家用来催化溶液中反应的标准方法并没有被酶所使用。这一点是通过考虑去溶化假说来说明的，并表明它不能解释在溶剂笼中相对于参考反应的相应kCage的kcat的大幅增加。还概述了与其他频繁调用的机制相关的问题。此外，还指出突变研究与基态失稳机制不一致。在考虑了没有通过进化优化的因素后，我们回顾了计算机模拟研究，这些研究再现了不同酶的整体催化效果。这些研究指出，静电效应是最重要的催化贡献。这种静电稳定机制的性质远不明显，因为反应体系与周围区域之间的静电相互作用在酶和溶液中是相似的。然而，不同的是，酶有一个预先组织的偶极环境，不需要支付重组能量来稳定相关的过渡态。显然，酶的催化能力以预先组织好的极性环境的形式储存在它们的折叠能量中。
The origin of the catalytic power of enzymes is discussed, paying attention to evolutionary constraints. It is pointed out that enzyme catalysis reflects energy contributions that cannot be determined uniquely by current experimental approaches without augmenting the analysis by computer simulation studies. The use of energy considerations and computer simulations allows one to exclude many of the popular proposals for the way enzymes work. It appears that the standard approaches used by organic chemists to catalyze reactions in solutions are not used by enzymes. This point is illustrated by considering the desolvation hypothesis and showing that it cannot account for a large increase in kcat relative to the corresponding kcage for the reference reaction in a solvent cage. The problems associated with other frequently invoked mechanisms also are outlined. Furthermore, it is pointed out that mutation studies are inconsistent with ground state destabilization mechanisms. After considering factors that were not optimized by evolution, we review computer simulation studies that reproduced the overall catalytic effect of different enzymes. These studies pointed toward electrostatic effects as the most important catalytic contributions. The nature of this electrostatic stabilization mechanism is far from being obvious because the electrostatic interaction between the reacting system and the surrounding area is similar in enzymes and in solution. However, the difference is that enzymes have a preorganized dipolar environment that does not have to pay the reorganization energy for stabilizing the relevant transition states. Apparently, the catalytic power of enzymes is stored in their folding energy in the form of the preorganized polar environment.