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)
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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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
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
Kazi, Rashek; Dai, Jian; Sweeney, Cameron et al. (2014) Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents. Nat Neurosci 17:914-22
Pang, Xiaodong; Zhou, Huan-Xiang (2014) Design rules for selective binding of nuclear localization signals to minor site of importin ?. PLoS One 9:e91025
Zhou, Huan-Xiang; Bilsel, Osman (2014) SAXS/SANS probe of intermolecular interactions in concentrated protein solutions. Biophys J 106:771-3
Zhou, Huan-Xiang (2014) Theoretical frameworks for multiscale modeling and simulation. Curr Opin Struct Biol 25:67-76
Cormier, Ashley R; Pang, Xiaodong; Zimmerman, Maxwell I et al. (2013) Molecular structure of RADA16-I designer self-assembling peptide nanofibers. ACS Nano 7:7562-72
Pang, Xiaodong; Zhou, Huan-Xiang (2013) Activation of signaling receptors: do ligands bind to receptor monomer, dimer, or both? BMC Biophys 6:7
Zhou, Huan-Xiang (2013) Influence of crowded cellular environments on protein folding, binding, and oligomerization: biological consequences and potentials of atomistic modeling. FEBS Lett 587:1053-61
Heymann, Gabriel; Dai, Jian; Li, Mufeng et al. (2013) Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels. Proc Natl Acad Sci U S A 110:E4045-54

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