Warshel A, Florián J
Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1062, USA.
Proc Natl Acad Sci U S A. 1998 May 26;95(11):5950-5. doi: 10.1073/pnas.95.11.5950.
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.
本文讨论了酶催化能力的起源，并关注了进化限制因素。文中指出，酶催化反映了能量贡献，而在不借助计算机模拟研究增强分析的情况下，当前实验方法无法唯一确定这些能量贡献。运用能量考量和计算机模拟，能够排除许多关于酶作用方式的流行观点。看起来，有机化学家在溶液中催化反应所采用的标准方法，酶并不使用。通过考虑去溶剂化假说并表明它无法解释相对于溶剂笼中参考反应相应的k笼而言，k催化的大幅增加这一点，对此进行了说明。还概述了与其他经常被提及的机制相关的问题。此外，文中指出突变研究与基态去稳定化机制不一致。在考虑了未被进化优化的因素之后，我们回顾了重现不同酶整体催化效果的计算机模拟研究。这些研究表明静电效应是最重要的催化贡献。这种静电稳定机制的本质远非显而易见，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，不同之处在于酶具有预先组织好的偶极环境，该环境无需为稳定相关过渡态支付重组能。显然，酶的催化能力以预先组织好的极性环境的形式存储在其折叠能中。
