Nanoscale dynamics and molecular recognition kinetics of a disordered protein

纳米尺度的蛋白质运动控制着大分子机制的组装和作用，如受体信号、蛋白质合成和DNA复制。然而，由于缺乏适用的实验方法，纳米尺度的蛋白质动力学在很大程度上仍然是一个未被探索的前沿。这项研究将使用一种新的技术，中子自旋回波谱(NSE)和理论物理来揭示纳米尺度的蛋白质动力学。此外，研究人员将研究纳米尺度的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级蛋白质运动的作用的理解。它还将证明，NSE可以为蛋白质分子机器的机制提供独特和重要的新见解。该计划将为培养年轻科学家提供机会，并提供将材料整合到分子生物物理学的本科生和研究生课程中的机会。本研究项目的具体目标是确定具有明显无序区域的柔性蛋白质中纳米尺度的蛋白质运动与蛋白质结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)技术来确定纳米尺度的蛋白质运动，并利用他们涉及非平衡统计力学的新理论物理框架来解释NSE数据。通过结合NSE和蛋白质结合动力学实验，这个小组将证明静电相互作用激活和控制固有无序蛋白质的纳米级动力学，这反过来又调节结合伙伴的结合动力学。理论物理分析将证明，NSE实验可以以高度具体的方式精确地定位纳米尺度的动力学变化。该小组将对一种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，以证明纳米尺度蛋白质动力学是蛋白质结合动力学中的控制(和可控)因素的假设。这项研究将在纳米尺度的蛋白质动力学动力学结合速率常数之间建立牢固的关系，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。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.