Modeling Crowding and Confinement of Cellular Environments

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DESCRIPTION (provided by applicant): The crowded environments inside cellular compartments are very different from the typical dilute conditions of in vitro and in silico biophysical studies of biomolecular systems. The long-term objective of this project is to bridge the in vitro-in vivo gap, by quantitatively reconstructing the influences of cellular environments on the thermodynamic and kinetic properties of biomolecules. Exploiting tremendous opportunities opened by our postprocessing approach for modeling effects of crowded cell-like environments and other recent advances, in this project we will (1) advance FFT-based postprocessing to achieve high accuracy in modeling crowding; (2) quantitatively delineate temperature dependence of crowding effects; and (3) characterize conformational ensembles and binding of intrinsically disordered proteins under crowding. Through capitalizing on FFT-based postprocessing and carrying out our own wet-lab studies, we will closely integrate computation and experiment to overcome challenges toward gaining insights into in vivo biochemical processes. The ability afforded by this research to use dilute-solution experiments and simulations for predicting the conformational ensembles of intrinsically disordered proteins under cell-like conditions will move us forward in elucidating their cellular functions. The conceptual advance that macromolecular crowding in cellular environments may serve as an important factor for protein stability in thermophiles could have broad implications for protein evolution and design.