Protein Dynamics in Enzymatic Catalysis

酶催化中的蛋白质动力学

• 批准号: 7817137
• 负责人: Robert Callender
• 金额: $ 187.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817137
• 关键词: Address; Affect; Architecture; Binding; Biochemical Reaction; Catalysis; Complex; Coupled; DHFR gene; Dihydrofolate Reductase; Drug Design; Enzymes; Equipment; Evolution; Goals; Grant; Knowledge; Lactate Dehydrogenase; Maps; Modeling; Motion; Mutation; Nature; Pharmaceutical Preparations; Pharmacologic Substance; Probability; Process; Protein Dynamics; Protein Engineering; Proteins; Protons; Purine-Nucleoside Phosphorylase; Reaction; Research; Role; Structure; System; Time; Ursidae Family; catalyst; design; enzyme substrate; instrumentation; millisecond; programs; protein structure; public health relevance; research study; theories; vibration

DESCRIPTION (provided by applicant): The goal of this Program Project, entitled Protein Dynamics in Enzymatic Catalysis, is to study atomic motion in enzymes. We propose to study concepts of how the dynamical nature of proteins affects enzymic function and the energy landscape of enzymes from enzyme-substrate to on-enzyme transition state transition state formation. We bring together a skilled research group of diverse backgrounds all aimed at understanding enzyme function. Importantly, we bring to bear unique, advanced, and effective experimental and theoretical approaches sensitive to the evolution of protein structure on multiple time scales, from ps to minutes. There are four projects and two cores. Project 1: 'Energy Landscapes Encoding Function in LDH Investigated Over Broad Time Scales' will (1) probe how conformational motion from picoseconds to milliseconds contributes transition state formation in lactate dehydrogenase and how motions on different timescales are related to each other and (2) probe the contribution of promoting vibrations to enzymic catalysis. Project 2: 'Dynamics and the Transition State of Purine Nucleoside Phosphorylase' studies (1) the motions leading to transition state formation in PNP and (2) the nature of the transition state in PNP by locating and characterizing dynamic promoting vibrations and by generating a vibrationally altered enzyme whose local and collective bond dynamics alter the probability of reaching the transition state. Project 3: 'Mapping the Energy Landscape of Catalysis in DHFR' aims to (1) determine the dynamics of substrate binding and Michaelis complex formation and coupled protein motions in dihydrofolate reductase; (2) determine the dynamics of proton transfer in DHFR; and (3) determine the role of promoting vibrations in the catalytic reaction of DHFR. Project 4: 'Energy Landscapes and Motional Timescales in Enzyme Catalysis' investigates dynamics in enzymes on multiple time scales and provides theoretical support to the other projects by (1) investigating how longer time conformational motion contributes to enzyme function, and in atomic detail, how motions at different timescales are related to each other; (2) determining how protein architecture results in vibrational energy "channeling" in enzymes and study how mutation effects this architecture; and (3) elucidating the concept of the tight binding of the transition state and show how, in a specific reaction, the transition state is approached and transited. The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. PUBLIC HEALTH RELEVANCE: Enzymes are targets for a broad array of Pharmaceuticals. How atomic motion in proteins brings about enzymatic catalysis is very poorly understood. The detailed structure of the enzymatic transition state is a powerful target for drug design, and increased knowledge of how enzymes form this state is fundamental for all catalysts and specifically for designing new classes of drugs.

描述（由申请人提供）：该程序项目的目标是酶促催化中的蛋白质动力学，是研究酶中的原子运动。我们建议研究蛋白质的动力学性质如何影响酶功能以及从酶 - 基底到酶内酶过渡状态过渡状态形成的酶的能量景观。我们汇集了一个熟练的研究小组，这些研究小组旨在了解酶功能。重要的是，我们带来了从PS到分钟的多个时间尺度上对蛋白质结构的演变敏感的独特，先进和有效的实验和理论方法。有四个项目和两个核心。项目1：“能源景观编码在LDH中的编码功能在广泛的时间尺度上进行了研究”（1）探测从picseconds到毫秒到毫秒的构象运动如何促进乳酸脱氢酶的过渡状态形成以及不同时间标准上的运动与彼此之间的相关性以及（2）探测促进纤维造成振动的贡献。项目2：“嘌呤核苷磷酸化酶的动力学和过渡状态”研究（1）通过定位和表征动态促进振动和表征动态振动的动态，导致PNP中过渡状态形成的运动性质，通过产生振动的酶变化，其当地和集体键合的动力学均改变了跨度的动力学。项目3：“映射DHFR中催化的能量局势”的目的是（1）确定底物结合的动力学和Michaelis复合物形成的动力学以及二氢叶酸还原酶中的蛋白质运动； （2）确定DHFR中质子转移的动力学； （3）确定促进振动在DHFR催化反应中的作用。项目4：“酶催化中的能量景观和运动时间尺度”研究了多个时间尺度上酶的动态，并通过（1）研​​究时间构象运动对酶功能的较长时间以及在不同时间上的运动与其他对方相关的酶功能的时间更长，从而为其他项目提供了理论支持； （2）确定蛋白质结构如何导致酶中的振动能“通道”，并研究突变如何影响该体系结构； （3）阐明过渡状态紧密结合的概念，并在特定的反应中显示过渡态如何接近和转移。设备核心（核心A）支持该程序专门的综合仪器套件。管理核心（核心B）管理程序项目。 公共卫生相关性：酶是各种各样的药物的靶标。蛋白质中的原子运动如何引起酶促催化的理解很少。酶促过渡状态的详细结构是药物设计的有力目标，并且对酶形成该状态的形成如何对所有催化剂来说是基础，特别是针对设计新类药物的基础。