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:
  • 金额:
    $ 55.91万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Quantifying the Relationship between Conformational Dynamics and Enzymatic Activity in Ribonuclease HI Homologues.
  • DOI:
    10.1021/acs.biochem.0c00500
  • 发表时间:
    2020-09-08
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Martin JA;Robustelli P;Palmer AG 3rd
  • 通讯作者:
    Palmer AG 3rd
Algebraic expressions for Carr-Purcell-Meiboom-Gill relaxation dispersion for N-site chemical exchange.
Compact expressions for R1ρ relaxation for N-site chemical exchange using Schur decomposition.
使用 Schur 分解的 N 位化学交换的 R1Ï 弛豫的紧凑表达式。
Comparisons of Ribonuclease HI Homologs and Mutants Uncover a Multistate Model for Substrate Recognition.
  • DOI:
    10.1021/jacs.1c11897
  • 发表时间:
    2022-03-30
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Martin, James A.;Palmer, Arthur G., III
  • 通讯作者:
    Palmer, Arthur G., III
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ARTHUR G PALMER其他文献

ARTHUR G PALMER的其他文献

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{{ truncateString('ARTHUR G PALMER', 18)}}的其他基金

Acquisition of an 800 MHz NMR Spectrometer Console and Probes
采购 800 MHz NMR 波谱仪控制台和探头
  • 批准号:
    10632877
  • 财政年份:
    2023
  • 资助金额:
    $ 55.91万
  • 项目类别:
RM1 Center on Macromolecular Dynamics by NMR Spectroscopy at the New York Structural Biology Center (CoMD/NMR)
纽约结构生物学中心 (CoMD/NMR) 的 RM1 核磁共振波谱大分子动力学中心
  • 批准号:
    10654062
  • 财政年份:
    2022
  • 资助金额:
    $ 55.91万
  • 项目类别:
RM1 Center on Macromolecular Dynamics by NMR Spectroscopy at the New York Structural Biology Center (CoMD/NMR)
纽约结构生物学中心 (CoMD/NMR) 的 RM1 核磁共振波谱大分子动力学中心
  • 批准号:
    10412493
  • 财政年份:
    2022
  • 资助金额:
    $ 55.91万
  • 项目类别:
Acquisition of a 900 MHz NMR Spectrometer Console and Probes
采购 900 MHz NMR 波谱仪控制台和探头
  • 批准号:
    10176998
  • 财政年份:
    2021
  • 资助金额:
    $ 55.91万
  • 项目类别:
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
  • 批准号:
    10318591
  • 财政年份:
    2019
  • 资助金额:
    $ 55.91万
  • 项目类别:
TR&D4: Integrated pipeline for data analysis
TR
  • 批准号:
    10194536
  • 财政年份:
    2017
  • 资助金额:
    $ 55.91万
  • 项目类别:
TR&D1: Experimental design in solution NMR spectroscopy
TR
  • 批准号:
    10194533
  • 财政年份:
    2017
  • 资助金额:
    $ 55.91万
  • 项目类别:
TR&D3: Experimental design in solid-state NMR spectroscopy
TR
  • 批准号:
    10194535
  • 财政年份:
    2017
  • 资助金额:
    $ 55.91万
  • 项目类别:
Center on Macromolecular Dynamics by NMR Spectroscopy
核磁共振波谱大分子动力学中心
  • 批准号:
    10400388
  • 财政年份:
    2017
  • 资助金额:
    $ 55.91万
  • 项目类别:
Center on Macromolecular Dynamics by NMR Spectroscopy
核磁共振波谱大分子动力学中心
  • 批准号:
    10194529
  • 财政年份:
    2017
  • 资助金额:
    $ 55.91万
  • 项目类别:

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