Protein Dynamics in Enzymatic Catalysis

描述（由申请人提供）：本项目名为酶催化中的蛋白质动力学，旨在了解原子运动如何影响酶催化。我们建议研究蛋白质-配体配合物在酶-底物和酶-产物之间的反应坐标上的结构演变。在这项研究中，如何动态性质的蛋白质影响酶的功能的概念进行了探讨。我们汇集了一个由专门研究动力学理论、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、合成有机化学家和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。

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.