Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
J Phys Chem B. 2010 Sep 2;114(34):11303-14. doi: 10.1021/jp104069t.
Combined quantum mechanics/molecular mechanics (QM/MM) calculations with high levels of correlated ab initio theory can now provide benchmarks for enzyme-catalyzed reactions. Here, we use such methods to test various QM/MM methods and the sensitivity of the results to details of the models for an important enzyme reaction, proton abstraction from acetyl-coenzyme A in citrate synthase. We calculate multiple QM/MM potential energy surfaces up to the local coupled cluster theory (LCCSD(T0)) level, with structures optimized at hybrid density functional theory and Hartree-Fock levels. The influence of QM methods, basis sets, and QM region size is shown to be significant. Correlated ab initio QM/MM calculations give barriers in agreement with experiment for formation of the acetyl-CoA enolate intermediate. In contrast, B3LYP fails to identify the enolate as an intermediate, whereas BH&HLYP does. The results indicate that QM/MM methods and setup should be tested, ideally using high-level calculations, to draw reliable mechanistic conclusions.
现在，结合量子力学/分子力学（QM/MM）计算和高相关的从头算理论可以为酶催化反应提供基准。在这里，我们使用这些方法来测试各种 QM/MM 方法和结果对柠檬酸合酶中重要酶反应质子提取模型细节的敏感性。我们计算了多个 QM/MM 势能表面，直到局部耦合簇理论（LCCSD(T0)）水平，结构在混合密度泛函理论和 Hartree-Fock 水平上进行优化。结果表明，QM 方法、基组和 QM 区域大小的影响非常显著。相关的从头算 QM/MM 计算给出了与实验一致的乙酰辅酶 A 烯醇化物中间体形成的能垒。相比之下，B3LYP 未能将烯醇化物识别为中间体，而 BH&HLYP 则可以。结果表明，QM/MM 方法和设置应该进行测试，理想情况下使用高水平的计算，以得出可靠的机械结论。
