The crowded and compartmentized environments inside cells are very different from the typical dilute conditions of in vitro and in silico biophysical studies of biomacromolecules. The long-term objectives of this project are to address the fundamental questions of how and how much macromolecular crowding and confinement affect thermodynamic and kinetic properties of biomolecules and to quantitatively reconstruct the influences of in vivo environments on these properties. The project has three integral components.
Aim 1 is to develop realistic theoretical models for crowding, which provide physical insight and yet allow for incorporation of molecular details.
Aim 2 is to carry out simulations and calculations for the interactions of proteins with atomistically detailed crowders, thereby direct quantitative comparison with in vitro experiments can be made.
Aim 3 is to validate theoretical predictions by in vitro experiments. Test problems encompass effects of crowding on the thermodynamics and kinetics of protein folding and protein binding. This project will overcome some of the major limitations of current approaches and make significant advances toward quantitatively reconstructing the influences of in vivo environments.

Public Health Relevance

The proposed research will lead to a deeper understanding of biological processes inside cells and of pathological conditions such as Parkinson's disease in particular. This understanding may form the foundation for more accurate prognoses of and better therapies against such diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
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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