Protein Dynamics in Enzymatic Catalysis

酶催化中的蛋白质动力学

基本信息

批准号：
7054046
负责人：
Robert Callender
金额：
$ 147.72万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2004-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7054046
关键词：
catalyst chemical transfer reaction electronic spectra enzyme structure enzymes intermolecular interaction molecular dynamics protein structure function

项目摘要

DESCRIPTION (provided by applicant): The goal of this Program Project, entitled Protein Dynamics in Enzymatic Catalysis, is to understand how atomic motion affects enzymatic catalysis. We propose to study the evolution of structure of protein-ligand complexes as the system moves along the reaction coordinate between enzyme-substrate and enzyme-product. In this study, concepts of how the dynamical nature of proteins affects enzymic function are explored. We bring together a research group consisting of researchers specializing in the theory of dynamics, computational chemistry, spectroscopy with broad time-resolution, enzymatic chemical mechanisms, protein chemistry and labeling, synthetic organic chemists, and transition state formation and structure. There are four projects and three cores. Project 1: Protein Dynamics in Catalysis by LDH and DHFR (Callender, PI) will examine the motions and time scales of how substrates and cofactors are brought together with important protein residues to bring about hydride and proton transfer in NAD(P)-linked enzymes using lactate dehydrogenase and dihydrofolate reductase as model enzymes. Project 2: Coordination of Protein Dynamics and Chemistry in PNP (Schramm) studies purine nucleoside phosphorylase in a program aimed at characterizing the dynamics of the substrate-enzyme system as it develops along the reaction pathway from Michaelis complex to transition state. Project 3: Proton Transfer Dynamics in Heme-Copper Oxidases (Dyer) is an investigation of the protein structures and evolution of these structures as the heme-copper oxidases bring about redox driven proton pumping. Project 4: Promoting Vibrations in LDH and PNP (Schwartz) examines whether or not protein dynamics has a direct role in the catalysis of bond formation and cleavage by studying how and to what extent the rapid motion of promoting vibrations couple to reaction dynamics in the enzyme-catalyzed reactions of LDH and PNP. The findings will be subjected to experimental investigation. The Chemistry Core (Core A) is designed to supply the proteins, mutants, and site specific isotopic labeled proteins and small molecules needed by the experimental studies. The Equipment Core (Core B) supports the temperature jump relaxation and difference spectrometers required of most of the experimental studies to characterize protein-ligand complex motion at the atomic level.

描述（由申请人提供）：该项目名为“酶催化中的蛋白质动力学”，其目标是了解原子运动如何影响酶催化。我们建议研究当系统沿着酶-底物和酶-产物之间的反应坐标移动时蛋白质-配体复合物结构的演变。在这项研究中，探讨了蛋白质的动力学性质如何影响酶功能的概念。我们汇集了一个由动力学理论、计算化学、宽时间分辨率光谱学、酶化学机制、蛋白质化学和标记、合成有机化学家以及过渡态形成和结构的研究人员组成的研究小组。有四个项目和三个核心。项目 1：LDH 和 DHFR 催化中的蛋白质动力学（Callender，PI）将研究底物和辅因子如何与重要的蛋白质残基结合在一起以在 NAD(P) 连接酶中实现氢化物和质子转移的运动和时间尺度使用乳酸脱氢酶和二氢叶酸还原酶作为模型酶。项目 2：PNP 中蛋白质动力学和化学的协调 (Schramm) 在一个程序中研究嘌呤核苷磷酸化酶，旨在表征底物-酶系统沿着从米氏复合体到过渡态的反应途径发展的动力学。项目 3：血红素铜氧化酶中的质子转移动力学 (Dyer) 是对蛋白质结构和这些结构的演化的研究，因为血红素铜氧化酶带来氧化还原驱动的质子泵送。项目 4：促进 LDH 和 PNP 中的振动（Schwartz）通过研究促进振动的快速运动如何以及在多大程度上与酶中的反应动力学耦合，研究蛋白质动力学是否在键形成和断裂的催化中具有直接作用-LDH和PNP的催化反应。调查结果将接受实验研究。化学核心（核心 A）旨在提供实验研究所需的蛋白质、突变体和位点特异性同位素标记蛋白质和小分子。设备核心（核心 B）支持大多数实验研究所需的温跃弛豫和差分光谱仪，以在原子水平上表征蛋白质-配体复合运动。