Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions.
Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions.
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DOI：
10.1021/ar900171c
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发表时间：
2010-01-19
影响因子：
18.3
通讯作者：
Jorgensen WL
中科院分区：
文献类型：
--
作者：
Acevedo O;Jorgensen WL
量子与分子力学（QM/MM）联合方法的应用重点是预测有机和酶促反应的激活势垒和稳态点结构。表征稳定溶液和酶活性位点过渡结构的因素为催化剂的设计和优化提供了基础。持续的技术进步允许从原型案例扩展到具有详细酶和凝聚相环境的机制研究，并充分集成了QM计算和配置采样。这需要改进算法，以快速QM方法为特征，在计算自由能变化（包括自由能摄动（FEP）计算）方面取得进展，并增强构型采样。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）模拟中结合动态QM，以及用于有效模拟质子转移反应的多项式正交方法。此QM/MM/MC/FEP方法的实用性说明了各种有机反应，包括取代，脱羧，消除和周环反应。通过与介质效应动力学实验结果的比较，验证了QM/MM方法在烃类、水、离子液体等各种溶剂中的准确性。从头算和密度泛函理论（DFT）方法与基于连续的溶剂化处理的相应结果揭示了缺陷，特别是对于质子溶剂。本文还总结了QM/MM在生物分子体系中的三个具体应用：(1)最近的一项研究阐明了2-吡啶衍生物在巨磷酸合成酶催化下作为串联Michael-aldol序列而不是Diels-Alder反应的机理；(2)阐明了一种罕见的ser - ser - lyss蛋白水解酶脂肪酸酰胺水解酶（FAAH）的作用机制；(3)构建Kemp消除5-硝基苯并异恶唑酶，突出了QM/MM在人工酶设计中的实用性。
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 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 semiempirical QM method, computation of multidimensional 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. Comparison with 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.
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影响因子：
15
作者：
Alexandrova, Anastassia N.;Roethlisberger, Daniela;Baker, David;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
3.3
作者：
Alexandrova, Anastassia N.;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
4.4
作者：
BERGSMA, JP;GERTNER, BJ;HYNES, JT
通讯作者：
HYNES, JT
影响因子：
1.8
作者：
ENGBERTS, JBFN
通讯作者：
ENGBERTS, JBFN
影响因子：
5.5
作者：
Acevedo, Orlando;Jorgensen, William L.;Evanseck, Jeffrey D.
通讯作者：
Evanseck, Jeffrey D.