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.

Public Health Relevance

Many intrinsically disordered proteins are linked to human diseases (e.g., Parkinson's disease). The proposed research will move us forward in elucidating their cellular functions, resulting in better understanding of disease mechanisms and stronger foundation for design therapies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wehrle, Janna P
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Florida State University
Schools of Arts and Sciences
United States
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Zhou, Huan-Xiang; Pang, Xiaodong (2018) Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation. Chem Rev 118:1691-1741
Banks, Anthony; Qin, Sanbo; Weiss, Kevin L et al. (2018) Intrinsically Disordered Protein Exhibits Both Compaction and Expansion under Macromolecular Crowding. Biophys J 114:1067-1079
Pang, Xiaodong; Zhou, Huan-Xiang (2017) Rate Constants and Mechanisms of Protein-Ligand Binding. Annu Rev Biophys 46:105-130
Qin, Sanbo; Zhou, Huan-Xiang (2017) Protein folding, binding, and droplet formation in cell-like conditions. Curr Opin Struct Biol 43:28-37
Im, Wonpil; Liang, Jie; Olson, Arthur et al. (2016) Challenges in structural approaches to cell modeling. J Mol Biol 428:2943-64
Qin, Sanbo; Zhou, Huan-Xiang (2016) Fast Method for Computing Chemical Potentials and Liquid-Liquid Phase Equilibria of Macromolecular Solutions. J Phys Chem B 120:8164-74
Jean-Francois, Frantz L; Dai, Jian; Yu, Lu et al. (2014) Binding of MgtR, a Salmonella transmembrane regulatory peptide, to MgtC, a Mycobacterium tuberculosis virulence factor: a structural study. J Mol Biol 426:436-46
Zhou, Huan-Xiang; Bilsel, Osman (2014) SAXS/SANS probe of intermolecular interactions in concentrated protein solutions. Biophys J 106:771-3
Dai, Jian; Zhou, Huan-Xiang (2014) General rules for the arrangements and gating motions of pore-lining helices in homomeric ion channels. Nat Commun 5:4641
Qin, Sanbo; Zhou, Huan-Xiang (2014) Further Development of the FFT-based Method for Atomistic Modeling of Protein Folding and Binding under Crowding: Optimization of Accuracy and Speed. J Chem Theory Comput 10:2824-2835

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