The association of proteins with small molecules and macromolecular targets is at the center of biology. The rates and mechanisms of these association processes constitute fundamental knowledge and provide avenues for designing therapeutic agents. The long-term objective of this project is the determination, via theory, simulation, and experiment, of association rates and mechanisms. Efforts in the pervious funding periods have culminated in the transient-complex theory. This computational methodology has allowed the protein association problem to be solved when the molecules are relatively rigid so that overall translational/rotational diffusion is rate- determining. The preset project aims to tackle the much more challenging problem where conformational change is closely coupled with the association process, and essential for biological function.
The specific aims are the determination of rate constants and mechanisms for three classes of systems: (1) protein-protein association;(2) protein-ligand binding;and (3) Site-specific protein-DNA binding. The research will integrate computation and experiment, and bring methodological breakthroughs that enable realistic modeling of conformational changes in calculating protein association rate constants. The knowledge gained will shed light on important protein functions and offer broad mechanistic insights.

Public Health Relevance

The proposed research will advance fundamental understanding on the association of proteins with small molecules and macromolecular targets. This understanding may provide new avenues for designing more selective drugs.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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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 (2016) Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating. Biophys J 111:1418-1428
Batra, Jyotica; Tjong, Harianto; Zhou, Huan-Xiang (2016) Electrostatic effects on the folding stability of FKBP12. Protein Eng Des Sel 29:301-8
Lensink, Marc F; Velankar, Sameer; Kryshtafovych, Andriy et al. (2016) Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment. Proteins 84 Suppl 1:323-48
Guo, Jingjing; Zhou, Huan-Xiang (2016) Protein Allostery and Conformational Dynamics. Chem Rev 116:6503-15
Gan, Quan; Dai, Jian; Zhou, Huan-Xiang et al. (2016) The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors. J Biol Chem 291:6595-606
Guo, Cong; Zhou, Huan-Xiang (2016) Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A. Proc Natl Acad Sci U S A 113:E6776-E6785
Pang, Xiaodong; Zhou, Huan-Xiang (2016) Mechanism and rate constants of the Cdc42 GTPase binding with intrinsically disordered effectors. Proteins 84:674-85
Guo, Jingjing; Zhou, Huan-Xiang (2016) Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism. Elife 5:
Dai, Jian; Wollmuth, Lonnie P; Zhou, Huan-Xiang (2015) Mechanism-Based Mathematical Model for Gating of Ionotropic Glutamate Receptors. J Phys Chem B 119:10934-40
Guo, Jingjing; Pang, Xiaodong; Zhou, Huan-Xiang (2015) Two pathways mediate interdomain allosteric regulation in pin1. Structure 23:237-47

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