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Nanoscale dynamics and molecular recognition kinetics of a disordered protein

无序蛋白质的纳米级动力学和分子识别动力学

基本信息

批准号：
1817684
负责人：
Zimei Bu
金额：
$ 65万
依托单位：
CUNY City College
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817684&HistoricalAwards=false
关键词：
Nanoscale dynamics molecular recognition kinetics

项目摘要

Nanoscale protein motions govern the assembly and actions of macromolecular machinery, such as receptor signaling, protein synthesis, and DNA replication. Nevertheless, nanoscale protein dynamics remains a largely unexplored frontier because of a paucity of applicable experimental methods. This research will employ a novel technique, neutron spin echo spectroscopy (NSE), and theoretical physics to reveal nanoscale protein dynamics. Further, the researchers will investigate how nanoscale protein motions influence the kinetics of protein-protein association. This research will improve our understanding of the role of nanoscale protein motions. It will also demonstrate that NSE can provide unique and important new insights into the mechanics of protein molecular machines. The program will provide opportunities for training young scientists, and provide opportunities to integrate materials into undergraduate and graduate courses on molecular biophysics. The specific goal of this research project is to determine the relationship between nanoscale protein motions and the protein association rate constant in flexible proteins with significantly disordered regions. This research group will apply neutron spin echo (NSE) technique to determine nanoscale protein motions, and utilize their novel theoretical physics framework involving non-equilibrium statistical mechanics to interpret the NSE data. By combining NSE and protein binding kinetics experiments, this group will demonstrate that electrostatic interactions activate and control nanoscale dynamics of an intrinsically disordered protein, which in turn modulates the binding kinetics of binding partners. Theoretical physics analyses will demonstrate that NSE experiments can pinpoint the nanoscale dynamics changes in a highly specific manner. The group will perform a series of structural, dynamics and kinetics experiments with an archetypical phosphorylated protein, in order to prove the hypothesis that nanoscale protein dynamics is a controlling (and controllable) factor in protein association kinetics. This research will establish a firm relationship between nanoscale protein dynamics kinetic association rate constants, in order to better model and predict the kinetics of molecular recognition of flexible and disordered proteins.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

纳米尺度的蛋白质运动控制着大分子机制的组装和行动，如受体信号传导、蛋白质合成和DNA复制。然而，由于缺乏适用的实验方法，纳米级蛋白质动力学仍然是一个未开发的前沿领域。这项研究将采用一种新的技术，中子自旋回波光谱（NSE）和理论物理来揭示纳米蛋白质动力学。此外，研究人员还将研究纳米级蛋白质运动如何影响蛋白质-蛋白质结合的动力学。这项研究将提高我们对纳米蛋白质运动作用的理解。它还将证明NSE可以为蛋白质分子机器的机制提供独特而重要的新见解。该计划将为培训年轻科学家提供机会，并提供机会将材料整合到分子生物物理学的本科生和研究生课程中。该研究项目的具体目标是确定具有显著无序区域的柔性蛋白质中纳米级蛋白质运动与蛋白质缔合速率常数之间的关系。该研究小组将应用中子自旋回波（NSE）技术来确定纳米蛋白质的运动，并利用他们的新理论物理框架，包括非平衡统计力学来解释NSE数据。通过结合NSE和蛋白质结合动力学实验，该小组将证明静电相互作用激活和控制内在无序蛋白质的纳米级动力学，从而调节结合伴侣的结合动力学。理论物理分析将证明NSE实验可以以高度特定的方式精确定位纳米级动力学变化。该小组将用典型的磷酸化蛋白质进行一系列结构，动力学和动力学实验，以证明纳米级蛋白质动力学是蛋白质缔合动力学的控制（和可控）因素的假设。这项研究将建立纳米级蛋白质动力学动力学关联速率常数之间的牢固关系，以便更好地建模和预测柔性和无序蛋白质的分子识别动力学。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。