Enzyme Catalysis & Bridged Bi-Metal Motif

酶催化

基本信息

批准号：
7161789
负责人：
MICHAEL L. KLEIN
金额：
$ 22.42万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2008-12-31
项目状态：
已结题

项目摘要

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.

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 方法进行计算机模拟，以补充宾夕法尼亚大学和其他地方的实验项目，重点关注酶催化。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选定示例。具体来说，将检查气单胞菌蛋白水解氨肽酶（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，还将探索甲烷单加氧酶（MMO）的催化机制，并对仿生 MMO 蛋白双金属核心的过氧化氢歧化和氧活化过程进行建模。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。这种理解将基于对不同环境中存在的共同主题的系统比较方法，并促进不同的反应过程。双金属基序的大量可用实验数据有助于对照研究，其价值将通过提出新实验并最终有助于设计针对此类酶的疗法的可能性而进一步增强。