Understanding allostery from the perspective of protein dynamics and energy flows

从蛋白质动力学和能量流的角度理解变构

• 批准号: 10372507
• 负责人: Ao Ma
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372507
• 关键词: Active Sites; Address; Affinity; Allosteric Site; Attention; Behavior; Binding; Catalysis; Coupled; Coupling; Cues; Disputes; Distal; Drug Design; Drug resistance; Entropy; Enzymes; Equilibrium; Global Change; HIV-1 protease; Intuition; Ligand Binding; Link; Methodology; Methods; Modeling; Molecular Conformation; Mutation; Nature; Pathway interactions; Process; Protein Analysis; Protein Dynamics; Protein Engineering; Proteins; Relaxation; Research; Signal Transduction; Signaling Protein; Structure; Surgical Flaps; System; Vertebral column; base; novel strategies; protein function; protein structure; prototype; resistance mutation; theories

Project Summary/Abstract Allostery is a fundamental aspect of protein function intrinsic to all proteins. It has important implications in enzyme catalysis, signal transduction, drug design and protein engineering. Understanding the mechanism of allostery is of fundamental importance. A rigorous understanding of its mechanism is of fundamental importance. The essence of allostery is that the binding of an effector to an allosteric site distal from the active site changes protein function (e.g. an increase in substrate affinity) at the active site. Two fundamental questions are central. 1) What is the change to the active site, induced by effector binding, that leads to the increased substrate affinity? This question concerns the nature of the allosteric signal. 2) How is the change at the allosteric site, introduced by effector binding, communicated to the active site? This question concerns the allosteric pathway. We propose a new approach to address both questions within a single unified framework: allosteric signal is a change in functional dynamics induced by effector-binding and allosteric pathway is the transition pathway of functional dynamics. The energy flow theory we developed provides us a rigorous approach to identify the pathway and mechanism of functional dynamics, hence the pathway and mechanism of allostery. We propose to apply the energy flow method to understand allostery in two representative systems. Aim 1: Identify the allosteric pathway in PDZ domain and elucidate its allosteric mechanism. PDZ domains are a prototype of “dynamic allostery” and attracted intensive attention. Allosteric residues identified by existing methods, however, cannot be identified with signal transduction of PDZ domain on a rigorous ground. Energy flow analysis on ligand-binding and energy relaxation in PDZ domain will enable us to rigorously determine its pathway for allostery and signal transduction. Aim 2: Identify the allosteric pathway responsible for non-active-site drug-resistant mutations in HIV-1 protease (HIV-PR) and elucidate the allosteric mechanism. Our Preliminary Results identified these residues as prominent players in the flap- opening dynamics, suggesting that their drug resistance is achieved via allostery.

项目摘要/摘要 变构是所有蛋白质固有的蛋白质功能的基本方面。它具有重要的含义 酶催化，信号转导，药物设计和蛋白质工程。了解机制 变构具有至关重要的重要性。对其机制的严格理解至关重要 重要性。变构的本质是，效应子与距离远端的变构位点的结合 活动位点会改变活性位点的蛋白质功能（例如底物亲和力的增加）。两个基本 问题是核心。 1）由效应子结合引起的活动位点的变化是什么，导致了 底物亲和力增加？这个问题涉及变构信号的性质。 2）变化如何 在由效应子绑定引入的变构位点，传达给活​​跃部位？这个问题涉及 变构途径。我们提出了一种新的方法来解决一个统一中的两个问题 框架：变构信号是效应器结合和变构引起的功能动力学的变化 途径是功能动力学的过渡途径。我们开发的能量流理论为我们提供了 一种严格的方法来识别功能动力学的途径和机制，因此途径和途径 变构的机制。 我们建议采用能量流方法来了解两个代表性系统中的变构。目的 1：确定PDZ结构域中的变构途径并阐明其变构机制。 PDZ域 是“动态变构”的原型，并引起了密集的关注。由 但是，在严格的地面上，无法通过PDZ域的信号传输来识别现有方法。 PDZ域中配体结合和能量放松的能量流分析将使我们能够严格 确定其变构和信号转导的途径。目标2：确定变构途径 负责HIV-1蛋白酶（HIV-PR）中的非活性药物抗药性突变并阐明 变构机制。我们的初步结果将这些残留物确定为襟翼中的杰出参与者 打开动力学，表明它们的耐药性是通过变构实现的。