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.
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.
|Qin, Sanbo; Zhou, Huan-Xiang (2016) 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|
|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|
|Pang, Xiaodong; Zhou, Huan-Xiang (2014) Design rules for selective binding of nuclear localization signals to minor site of importin Î±. PLoS One 9:e91025|
|Zhou, Huan-Xiang (2014) Theoretical frameworks for multiscale modeling and simulation. Curr Opin Struct Biol 25:67-76|
|Kazi, Rashek; Dai, Jian; Sweeney, Cameron et al. (2014) Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents. Nat Neurosci 17:914-22|
|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|
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