Warshel Arieh
Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA.
Annu Rev Biophys Biomol Struct. 2003;32:425-43. doi: 10.1146/annurev.biophys.32.110601.141807. Epub 2003 Feb 5.
Understanding the action of enzymes on an atomistic level is one of the important aims of modern biophysics. This review describes the state of the art in addressing this challenge by simulating enzymatic reactions. It considers different modeling methods including the empirical valence bond (EVB) and more standard molecular orbital quantum mechanics/molecular mechanics (QM/MM) methods. The importance of proper configurational averaging of QM/MM energies is emphasized, pointing out that at present such averages are performed most effectively by the EVB method. It is clarified that all properly conducted simulation studies have identified electrostatic preorganization effects as the source of enzyme catalysis. It is argued that the ability to simulate enzymatic reactions also provides the chance to examine the importance of nonelectrostatic contributions and the validity of the corresponding proposals. In fact, simulation studies have indicated that prominent proposals such as desolvation, steric strain, near attack conformation, entropy traps, and coherent dynamics do not account for a major part of the catalytic power of enzymes. Finally, it is pointed out that although some of the issues are likely to remain controversial for some time, computer modeling approaches can provide a powerful tool for understanding enzyme catalysis.
在原子层面理解酶的作用是现代生物物理学的重要目标之一。本综述描述了通过模拟酶促反应应对这一挑战的当前进展。它考虑了不同的建模方法，包括经验价键（EVB）和更标准的分子轨道量子力学/分子力学（QM/MM）方法。强调了对QM/MM能量进行适当构型平均的重要性，指出目前这种平均最有效地由EVB方法进行。阐明了所有正确进行的模拟研究都已将静电预组织效应确定为酶催化的来源。有人认为，模拟酶促反应的能力也提供了检验非静电贡献的重要性以及相应提议有效性的机会。事实上，模拟研究表明，诸如去溶剂化、空间应变、近攻击构象、熵阱和相干动力学等突出提议并不能解释酶催化能力的主要部分。最后指出，尽管其中一些问题可能在一段时间内仍存在争议，但计算机建模方法可为理解酶催化提供强大工具。
