Enzyme Catalysis & Bridged Bi-Metal Motif

描述(由申请人提供)：建议使用从头算(基于密度泛函理论)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计划。本提案的目的是使用最先进的计算方法来详细探索利用桥联双金属基序进行催化的酶的精选例子。具体地说，将研究气单胞菌蛋白水解酶(AAP)和精氨酸酶的机制模型，以及仿生变体的结构和动力学性质。计算研究将考察水解酶(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，还将探索甲烷单加氧酶(MMO)的催化机理，并对仿生MMO蛋白双金属核心的过氧化氢歧化和氧激活过程进行建模。长期目标是深入了解桥联双金属基序在氧化还原和水解酶催化中的作用以及微调。这一理解将基于对存在于不同环境中并促进不同反应过程的共同基序的系统比较方法。关于双金属基序的丰富的现有实验数据适合于一项对照研究，其价值将进一步提高，因为有可能提出新的实验，并最终有助于针对这种酶的疗法的设计。

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.