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
- 来源:
- 关键词:AddressBiological ProcessBiophysicsBreathingCadherinsCatalysisCell Adhesion MoleculesCore ProteinCoupledCouplingDNA Repair GeneDevelopmentDimerizationDiseaseEnzymesEquilibriumEventFeedbackFutureGoalsHealthHumanInvestigationKineticsLaboratoriesLigand BindingLigandsMeasurementModificationMolecularMolecular ConformationMotionMutationNMR SpectroscopyNucleic AcidsPathologyPharmacologic SubstanceProcessPropertyProtein DynamicsProteinsPsychological TechniquesRNAReactionRegulationRelaxationResearchResolutionRoleSiteStructureTechniquesbiological systemsconformational conversiondesignexosomeexperimental studygain of functionimprovedmacromoleculemembermolecular dynamicsmolecular recognitionnon-Nativenovelnucleic acid binding proteinnucleotidyltransferaseprogramsprotein activationprotein functionprotein protein interactionribonuclease H1theoriestranscription 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.
蛋白质的构象变化是几乎所有生物功能所必需的,
构象转变与许多病理学有关。综合实验
分子内动力学和分子间动力学对生物学的重要贡献的信息
蛋白质的功能对于平衡性质的生物物理理论至关重要,例如热容量和
热稳定性;用于动力学过程的机械解释,如酶催化和配体
识别;理解变构或调节中的“远距离作用”;以及设计新的蛋白质
和蛋白质配体,包括药剂。蛋白质的构象变化,包括局部
振动、环运动、结构域之间的相对运动、蛋白质核心的集体“呼吸”、配体-
结合或寡聚化反应,以及整个折叠-解折叠事件,可能是密切相关的,
在某些情况下,对生物学功能如分子识别的速率限制,沿着沿着
酶的催化循环,以及通过分子内或分子间的蛋白质-
蛋白质相互作用扰乱动力学过程和构象平衡的突变与
具有显著病理学,包括功能丧失或获得以及错误折叠。最近的事态发展,包括
这些来自PI实验室,为构象动力学的研究开辟了新的机会
在溶液中平衡时使用NMR自旋弛豫测量(和其他NMR可观测值)的方法
并且具有原子位置分辨率,而没有由非原生修改引入的潜在复杂性
其他溶液态光谱技术所必需的。此外,实验之间的紧密耦合
测量和分子动力学(MD)模拟或其它理论方法允许反馈
理论和实验之间的解释结果,制定假设正在进行的调查,
改进实验和理论技术。本提案将利用这些办法,
解释酶中构象转换的功能作用,包括核糖核酸酶HI(和其他
核苷酸转移酶超家族成员)、DNA修复蛋白AlkB和RNA外泌体;
Hox转录因子和其他核酸结合蛋白;以及蛋白质-蛋白质相互作用,包括
通过钙粘蛋白细胞粘附蛋白的链交换和二聚化。这些目标得到了以下方面的支持
开发了通过NMR光谱和MD表征蛋白质动力学的改进方法
仿真这项研究计划将在前所未有的详细水平上解释分子特征,
构象变化、动力学和动力学的基本原理,对于理解
蛋白质和其他大分子的正常和异常生物功能。完成这些目标
将使更多的未来应用于生物重要性的大分子系统的广泛范围。
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.
- DOI:10.1016/j.jmr.2020.106846
- 发表时间:2020-12
- 期刊:
- 影响因子:0
- 作者:Koss H;Rance M;Palmer AG 3rd
- 通讯作者:Palmer AG 3rd
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。
- DOI:10.1016/j.jmr.2020.106705
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Rance,Mark;Palmer3rd,ArthurG
- 通讯作者:Palmer3rd,ArthurG
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&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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