Department of Theoretical Chemistry, Lund University, Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.
J Phys Chem A. 2009 Oct 29;113(43):11793-800. doi: 10.1021/jp9029024.
A common approach for the computational modeling of enzyme reactions is to study a rather small model of the active site (20-200 atoms) with quantum mechanical (QM) methods, modeling the rest of the surroundings by a featureless continuum with a dielectric constant of approximately 4. In this paper, we discuss how the residues included in the QM model should be selected and how many residues need to be included before reaction energies converge. As a test case, we use a proton-transfer reaction between a first-sphere cysteine ligand and a second-sphere histidine group in the active site of [Ni,Fe] hydrogenase. We show that it is not a good approach to add groups according to their distance to the active site. A better approach is to add groups according to their contributions to the QM/MM energy difference. However, the energies can still vary by up to 50 kJ/mol for QM systems of sizes up to 230 atoms. In fact, the QM-only approach is based on the hope that a large number of sizable contributions will cancel. Interactions with neutral groups are, in general, short-ranged, with net energy contributions of less than 4 kJ/mol at distances above 5 A from the active site. Interactions with charged groups are much more long-ranged, and interactions with buried charges 20 A from the active site can still contribute by 5 kJ/mol to the reaction energy. Thus, to accurately model the influence of the surroundings on enzyme reaction energies, a detailed and unbiased atomistic account of the surroundings needs to be included.
一种用于酶反应计算建模的常见方法是使用量子力学 (QM) 方法研究活性位点的较小模型（20-200 个原子），通过介电常数约为 4 的无特征连续体来模拟周围环境的其余部分。在本文中，我们讨论了应如何选择包含在 QM 模型中的残基以及在反应能收敛之前需要包含多少残基。作为一个测试案例，我们使用 [Ni,Fe] 氢化酶活性位点中第一个球半胱氨酸配体和第二个球组氨酸之间的质子转移反应。我们表明，根据它们与活性位点的距离添加基团不是一个好方法。更好的方法是根据它们对 QM/MM 能量差的贡献来添加基团。然而，对于大小高达 230 个原子的 QM 系统，能量仍然可能变化高达 50 kJ/mol。实际上，QM 仅方法基于这样一种希望，即大量的大量贡献将相互抵消。与中性基团的相互作用通常是短程的，在距离活性位点 5 A 以上时，净能量贡献小于 4 kJ/mol。与带电基团的相互作用要长得多，距离活性位点 20 A 的埋置电荷的相互作用仍可以为反应能贡献 5 kJ/mol。因此，要准确模拟周围环境对酶反应能的影响，需要包含对周围环境的详细和无偏见的原子级描述。
