Computer Simulations of Enzymes

酶的计算机模拟

• 批准号: 6986136
• 负责人: Weitao Yang
• 金额: $ 22.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986136
• 关键词: X ray crystallography; aminoacid tRNA ligase; carboxylation; catalyst; cell cycle proteins; chemical reaction; computer simulation; conformation; cyclin dependent kinase; enzyme activity; enzyme mechanism; enzyme substrate complex; halogenation; isomerase; method development; phosphoprotein phosphatase; protein protein interaction; protein structure function; quantum chemistry; structural biology; tryptophan

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.

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。长期目标是开发和建立 QM/MM 模拟，作为酶结构和化学反应研究实验的平等伙伴，并深入了解生物系统中的化学反应机制。该项目有以下具体目标： 目标 1. 反应路径势（RPP）是沿着最小能量路径的量子力学和分子力学（QM/MM）组合势能的解析能量表达式。我们计划将 RPP 方法开发成一种实用工具，用于捕获化学过程和蛋白质构象变化之间的动态相互作用和相互作用，以进行酶反应模拟。目标 2. 我们将研究色氨酸-tRNA 合成酶 (TrpRS) 催化的氨基酸激活过程并解决以下问题：催化机制是缔合还是解离？与在多个 X 射线晶体学结构中观察到的构象变化相关的能量学和动力学变化有哪些？构象动力学与化学过程之间的耦合是什么？我们计划建立一种基于RPP的实用模拟方法来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，并全面了解 Cdc25B 与小分子底物磷酸苯酯及其蛋白质底物可能的反应机制。目标4.我们将研究4-草酰巴豆酸互变异构酶（4OT）催化的脱羧和脱卤反应的反应机制，并阐明蛋白质骨架在4OT催化中的作用。