Computer Simulations of Enzymes

描述（由申请人提供）：基于来自X射线和NMR实验的结构信息，使用分子动力学和量子力学/分子力学（QM/MM）方法进行的计算模拟能够描述酶催化的化学反应和氧化还原过程。从头算QM/MM方法利用了相关量子力学方法的准确性和可靠性，但与相应的半经验量子力学方法相比，计算成本要高得多。因此，基于从头算QM/MM方法的反应路径和自由能计算在模拟时间和相空间采样方面遇到了独特的挑战。本文旨在进一步发展量子化学从头算方法及其在重要酶的氧化还原过程和化学反应机理研究中的应用。长期目标是开发和建立基于密度泛函理论的QM/MM模拟，作为酶研究实验的平等伙伴，并提供生物系统中化学反应和氧化还原反应机制的详细见解。 最近发展了从头算QM/MM-MFEP方法，以克服以前的从头算QM/MM方法在获得最小能量反应路径时遇到的一些困难。本文的目的是将QM/MM-MFEP方法进一步发展成为一种全面而精确的方法，用于用从头算QM/MM方法模拟溶液和酶中的氧化还原过程。QM/MM方法将用于研究几个重要系统：（1）铜蛋白酶肽甘氨酸α-羟基化单加氧酶（PHM）的野生型和单位点变体的氧化还原电位，PHM是两种铜家族酶的原型，包括多巴胺β-单加氧酶和酪胺β-单加氧酶。(2)人类DNA聚合酶，催化DNA合成中的磷酰基转移反应。(3)硫酸酯酶，控制蛋白质、碳水化合物、脂质和类固醇的硫酸化状态，并且可以产生由任何酶产生的最大速率增强。(4)肽聚糖再循环酶，催化磷酰基转移和水解。 拟议的工作将导致理论和计算方法的进步和重要的酶反应机制的理解。此外，它还将有助于设计新药和酶抑制剂。

DESCRIPTION (provided by applicant): Based on structural information from X-ray and NMR experiments, computational simulations performed us- ing molecular dynamics and the quantum mechanical/molecular mechanical (QM/MM) approach are able to describe the chemical reactions and redox processes catalyzed by enzymes. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with corresponding semiempirical quantum mechanical ap- proaches. Thus reaction path and free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation times and phase space sampling. This proposal aims to develop further the ab initio QM/MM methodology and its application to the studies of redox processes and mechanisms of chemical reactions in important enzymes. The long-term goal is to develop and establish density functional theory-based QM/MM simulation as an equal partner with experiments for the study of enzymes and to provide detailed insight into chemical reaction and redox reaction mechanisms in biological systems. The ab initio QM/MM-MFEP method has been developed recently to overcome some of the difficul- ties encountered in previous ab initio QM/MM approaches for obtaining minimum energy reaction paths. This proposal aims to develop the QM/MM-MFEP method further into a comprehensive and accurate method for the simulation of redox processes in solution and in enzymes using ab initio QM/MM meth- ods. The QM/MM methodology will be used to investigate several important systems: (1) The redox poten- tials in wild-type and single-site variants of the copper protein enzyme peptidyglycine alpha-hydroxylating monooxygenase (PHM), which is a prototype for the two copper family enzymes that includes dopamine beta-monooxygenase and tyramine beta-monooxygenase. (2) Human DNA polymerase , which catalyzes the phosphoryl-transfer reaction in DNA synthesis. (3) Sulfatases, which controls the state of sulfation of proteins, carbohydrates, lipids and steroids, and may produce the largest rate enhancements that are generated by any enzyme. (4) Peptidoglycan recycling enzyme, which catalyze phosphoryl transfer and hydrolysis. The proposed work will lead to the advancement of theoretical and computational methodology and the understanding of important enzyme reaction mechanisms. In addition, it will also serve to aid in the design of new drugs and enzyme inhibitors.