Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, USA.
Acc Chem Res. 2010 Jan 19;43(1):142-51. doi: 10.1021/ar900171c.
Application of combined quantum and molecular mechanical (QM/MM) methods focuses on predicting activation barriers and the structures of stationary points for organic and enzymatic reactions. Characterization of the factors that stabilize transition structures in solution and in enzyme active sites provides a basis for design and optimization of catalysts. Continued technological advances allowed for expansion from prototypical cases to mechanistic studies featuring detailed enzyme and condensed-phase environments with full integration of the QM calculations and configurational sampling. This required improved algorithms featuring fast QM methods, advances in computing changes in free energies including free-energy perturbation (FEP) calculations, and enhanced configurational sampling. In particular, the present Account highlights development of the PDDG/PM3 semi-empirical QM method, computation of multi-dimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo (MC) simulations, and a polynomial quadrature method for efficient modeling of proton-transfer reactions. The utility of this QM/MM/MC/FEP methodology is illustrated for a variety of organic reactions including substitution, decarboxylation, elimination, and pericyclic reactions. A comparison to experimental kinetic results on medium effects has verified the accuracy of the QM/MM approach in the full range of solvents from hydrocarbons to water to ionic liquids. Corresponding results from ab initio and density functional theory (DFT) methods with continuum-based treatments of solvation reveal deficiencies, particularly for protic solvents. Also summarized in this Account are three specific QM/MM applications to biomolecular systems: (1) a recent study that clarified the mechanism for the reaction of 2-pyrone derivatives catalyzed by macrophomate synthase as a tandem Michael-aldol sequence rather than a Diels-Alder reaction, (2) elucidation of the mechanism of action of fatty acid amide hydrolase (FAAH), an unusual Ser-Ser-Lys proteolytic enzyme, and (3) the construction of enzymes for Kemp elimination of 5-nitrobenzisoxazole that highlights the utility of QM/MM in the design of artificial enzymes.
联合量子力学和分子力学（QM/MM）方法的应用主要集中在预测有机和酶反应的活化势垒和稳定点结构上。对稳定过渡态的因素进行特征描述，无论是在溶液中还是在酶活性中心，都为催化剂的设计和优化提供了依据。技术的不断进步使得从原型案例扩展到具有详细酶和凝聚相环境的机制研究成为可能，并且完全整合了 QM 计算和构象采样。这需要改进算法，包括快速 QM 方法、包括自由能微扰（FEP）计算在内的自由能变化的计算、以及增强的构象采样。特别是，本报告重点介绍了 PDDG/PM3 半经验 QM 方法的发展、多维平均力势（PMF）的计算、在蒙特卡罗（MC）模拟中即时 QM 的应用以及用于有效建模质子转移反应的多项式求积方法。该 QM/MM/MC/FEP 方法的实用性通过各种有机反应进行了说明，包括取代、脱羧、消除和周环反应。与中等效应的实验动力学结果的比较验证了 QM/MM 方法在从烃类到水到离子液体的所有溶剂范围内的准确性。与基于连续体的溶剂化处理的从头算和密度泛函理论（DFT）方法的相应结果表明了这些方法的缺陷，特别是对于质子溶剂。本报告还总结了三个特定的 QM/MM 生物分子系统应用：（1）最近的一项研究澄清了 2-吡喃酮衍生物在大霉素合酶催化下反应的机制，这是一个串联的迈克尔-丙醛序列，而不是 Diels-Alder 反应；（2）阐明了脂肪酸酰胺水解酶（FAAH）的作用机制，FAAH 是一种不寻常的 Ser-Ser-Lys 蛋白水解酶；（3）构建用于 5-硝基苯并异恶唑 Kemp 消除的酶，突出了 QM/MM 在人工酶设计中的应用。
