Nanoscale dynamics and molecular recognition kinetics of a disordered protein

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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.