Enzyme Catalysis & Bridged Bi-Metal Motif

描述（由申请人提供）：提出了使用从头算（基于密度泛函数理论）Car-Parinello分子动力学（CPMD）和混合量子CPMD /经典MD方法的计算机模拟，以补充宾夕法尼亚大学和其他地方专注于酶催化的实验项目。本提案的目的是使用最先进的计算方法来探索详细选择的酶的例子，利用桥接双金属基序催化。具体来说，将研究水解气单胞菌氨肽酶（AAP）和精氨酸酶的机制模型，以及仿生变体的结构和动力学特性。计算研究将研究水解酶（AAP）的金属和底物选择性，并比较锰过氧化氢酶和精氨酸酶的氧化还原过氧化氢酶活性。此外，通过模拟甲烷单加氧酶（MMO）蛋白双金属核心过氧化氢歧化和氧活化过程，探讨了甲烷单加氧酶（MMO）的催化机制。长期目标是深入了解桥接双金属基序在氧化还原和水解酶催化中的作用以及微调。这种理解将基于对出现在不同环境中并促进不同反应过程的共同母题的系统比较方法。关于双金属基序的丰富实验数据有助于进行对照研究，其价值将通过提出新实验的可能性进一步增强，并最终有助于设计针对此类酶的治疗方法。

DESCRIPTION (provided by applicant): Computer simulations using ab initio (density functional theory based) Car-Parinello molecular dynamics (CPMD) and hybrid quantum CPMD / classical MD methodologies are proposed to complement experimental programs at the University of Pennsylvania and elsewhere that focus on enzyme catalysis. The objective of the present proposal is to use state-of-the-art computational methods to explore in detail selected examples of enzymes that exploit the bridged bimetal motif for catalysis. Specifically, mechanistic models of Aeromonas proteolytica aminopeptidase (AAP) and arginase will be examined, as well as the structural and dynamical properties of biomimetic variants. The computational studies will investigate the metal and substrate selectivity of hydrolytic enzymes (AAP), and compare the redox catalase activity of manganese catalase and arginase. In addition, the catalytic mechanism of methane monooxygenase (MMO) will be explored along with modeling the hydrogen peroxide disproportionation and oxygen activation processes at the bimetal core of a biomimetic MMO protein. The long-term goal is to reach a deep understanding of the role of, as well as the fine tuning at, the bridged bimetal motif in redox and hydrolytic enzymatic catalysis. This understanding will be based on a systematic comparative approach to a common motif present in different environments and promoting different reaction processes. The wealth of available experimental data on the bimetal motif lends itself to a controlled study, whose value will be further enhanced by the possibility of suggesting new experiments and ultimately contributing to the design of therapies that target such enzymes.