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.

项目总结/文摘