Computer Simulations of Enzymes

酶的计算机模拟

• 批准号: 6872658
• 负责人: Weitao Yang
• 金额: $ 25.34万
• 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/6872658
• 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）：该提案旨在进一步发展QM/MM方法论及其应用于研究重要酶中化学反应机制的应用，并了解蛋白质构象动态在蛋白质功能中的作用。长期目标是开发和建立QM/MM模拟作为与酶研究结构和化学反应的实验的平等合作伙伴，并洞悉生物系统中化学反应机制。该项目具有以下特定目的：目标1。反应路径电势（RPP）是沿最小能量路径沿最小能量路径的量子力学和分子机械（QM/mm）组合的分析能表达。我们计划将RPP方法开发为一种实用工具，用于捕获化学过程和蛋白质构象变化的动态相互作用和相互作用的酶反应模拟。 AIM 2。我们将研究由色氨酸-TRNA合成酶（TRPRS）催化的氨基酸激活过程，并解决以下问题：催化机制是关联还是解离？能量和动力学的变化与在多个X射线晶体结构中观察到的构象变化相关？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的实用仿真方法，以研究蛋白质构象变化和动力学在酶促催化过程中的作用。 AIM 3。我们计划研究细胞分割周期25（CDC25B）磷酸酶的机制，并完整地描绘了Cdc25b与小分子底物苯基磷酸盐以及其蛋白质底物的可能反应机理的完整图片。 AIM 4。我们将研究由4-黑色素蛋白酶互变异酶（4OT）催化的脱羧和脱核反应的反应机制，并阐明了蛋白质主链在4OT催化中的作用。