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Macromolecular dynamics and conformational changes in biological function

生物功能中的大分子动力学和构象变化

基本信息

批准号：
10546431
负责人：
ARTHUR G PALMER
金额：
$ 55.91万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546431
关键词：
Address Biological Process Biophysics Breathing Cadherins Catalysis Cell Adhesion Molecules Core Protein Coupled Coupling DNA Repair Gene Development Dimerization Disease Enzymes Equilibrium Event Feedback Future Goals Health Human Investigation Kinetics Laboratories Ligand Binding Ligands Measurement Modification Molecular Molecular Conformation Motion Mutation NMR Spectroscopy Nucleic Acids Pathology Pharmacologic Substance Process Property Protein Dynamics Proteins Psychological Techniques RNA Reaction Regulation Relaxation Research Resolution Role Site Structure Techniques biological systems conformational conversion design exosome experimental study gain of function improved macromolecule member molecular dynamics molecular recognition non-Native novel nucleic acid binding protein nucleotidyltransferase programs protein activation protein function protein protein interaction ribonuclease H1 theories transcription factor

项目摘要

Conformational changes of proteins are required for nearly all biological functions and inappropriate conformational transitions are associated with numerous pathologies. Comprehensive experimental information on the essential contributions of intramolecular dynamics and intermolecular kinetics to biological functions of proteins is critical for biophysical theories of equilibrium properties, such as heat capacity and thermal stability; for mechanistic interpretations of kinetic processes, such as enzyme catalysis and ligand recognition; for understanding “action at a distance” in allostery or regulation; and for design of novel proteins and protein ligands, including pharmaceutical agents. Conformational changes in proteins, including local librations, loop motions, relative motions between domains, collective “breathing” of protein cores, ligand- binding or oligomerization reactions, and overall folding-unfolding events, may be closely coupled, and in some instances rate-limiting, to biological functions such as molecular recognition, transitions along the catalytic cycle of enzymes, and inhibition or activation of proteins through intra- or inter-molecular protein- protein interactions. Mutations that perturb dynamical processes and conformational equilibria are associated with significant pathology, including loss or gain of function and misfolding. Recent developments, including those from the PI laboratory, have opened new opportunities for investigation of conformational dynamic processes using NMR spin relaxation measurements (and other NMR observables) at equilibrium in solution and with atomic site resolution, without potential complications introduced by non-native modifications necessary for other solution-state spectroscopic techniques. In addition, close coupling between experimental measurements and molecular dynamics (MD) simulations or other theoretical approaches allow feedback between theory and experiment in interpreting results, formulating hypotheses for on-going investigation, and improving both experimental and theoretical techniques. The present proposal will use these approaches to explicate the functional roles of conformational transistions in enzymes, including ribonuclease HI (and other members of the nucleotidyl-transferase superfamily), the DNA-repair protein AlkB, and the RNA exosome; Hox transcription factors and other nucleic acid binding proteins; and protein-protein interactions, including strand-swapping and dimerization by cadherin cell-adhesion proteins. These objectives are supported by development of improved approaches for characterizing protein dynamics by NMR spectroscopy and MD simulation. This research program will explicate at a level of unprecedented detail molecular features and principles underlying conformational changes, dynamics, and kinetics that are critical for understanding normal and abnormal biological functions of proteins and other macromolecules. Completion of these goals will enable additional future applications to a wide range of macromolecular systems of biological importance.

蛋白质的构象变化几乎是所有生物功能所必需的