Computer Simulations of Enzymes

描述（由申请人提供）：本提案旨在进一步发展QM/MM方法及其应用，以研究重要酶的化学反应机制，并了解蛋白质构象动力学在蛋白质功能中的作用。长期目标是发展和建立QM/MM模拟，作为酶结构和化学反应研究的平等实验伙伴，并为生物系统中的化学反应机制提供见解。本项目有以下具体目标：目标1。反应路径势（RPP）是量子力学和分子力学（QM/MM）结合势能沿最小能量路径的解析能量表达式。我们计划将RPP方法发展成为一种实用的工具，用于捕获化学过程与蛋白质构象变化之间的动态相互作用和相互作用，用于酶反应模拟。目标2。我们将研究色氨酸- trna合成酶（trpr）催化的氨基酸活化过程，并解决以下问题：催化机制是结合的还是解离的？在多个x射线晶体结构中观察到的构象变化与能量学和动力学的变化有什么关系？构象动力学和化学过程之间的耦合是什么？我们计划建立一种基于RPP的实用模拟方法，研究蛋白质构象变化和动力学在酶催化过程中的作用。目标3。我们计划研究细胞分裂周期25 （Cdc25B）磷酸酶的机制，并对Cdc25B与小分子底物磷酸苯酯及其蛋白底物的可能反应机制进行全面的研究。目标4。我们将研究4-草叶糖醛酸互变异构体酶（4OT）催化脱羧和脱卤反应的反应机理，并阐明蛋白骨架在4OT催化中的作用。

DESCRIPTION (provided by applicant): This proposal aims at further development in the QM/MM methodology and its application to investigate the mechanism of chemical reactions in important enzymes and to understand the role of protein conformation dynamics in protein functions. The long-term goal is to develop and establish the QM/MM simulation as an equal partner with experiments for the study of structure and chemical reactions in enzymes and to provide insight into chemical reaction mechanisms in biological systems. This project has the following specific aims: Aim 1. The reaction path potential (RPP) is an analytical energy expression of the combined quantum mechanical and molecular mechanical (QM/MM) potential energy along the minimum energy path. We plan to develop the RPP method into a practical tool for capturing the dynamic interaction and interplay between the chemical process and the protein conformation changes for enzyme reaction simulation. Aim 2. We will investigate the amino acid activation process catalyzed by tryptophanyl-tRNA synthetase (TrpRS) and address the following questions: Is the catalytic mechanism associative or dissociative? What are the changes of energetics and dynamics correlated to the conformational changes observed in multiple X-ray crystallography structures? What is the coupling between the conformational dynamics and the chemical process? We plan to build a practical simulation method based on RPP to study the role of protein conformation changes and dynamics in enzymatic catalysis process. Aim 3. We plan to investigate the mechanism of cell-division cycle25 (Cdc25B) phosphatase and generate a complete picture of the possible reaction mechanisms of Cdc25B with the small molecule substrate phenyl phosphate and also with its protein substrate. Aim 4. We will investigate the reaction mechanism for the decarboxylation and dehalogenation reactions catalyzed by 4-Oxalocrotonate tautomerase (4OT) and elucidate the role of protein backbone in 4OT catalysis.