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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Guo, Jingjing; Pang, Xiaodong; Zhou, Huan-Xiang (2015) Two pathways mediate interdomain allosteric regulation in pin1. Structure 23:237-47
Dai, Jian; Zhou, Huan-Xiang (2015) Reduced curvature of ligand-binding domain free-energy surface underlies partial agonism at NMDA receptors. Structure 23:228-36
Berezhkovskii, Alexander M; Szabo, Attila; Greives, Nicholas et al. (2014) Multidimensional reaction rate theory with anisotropic diffusion. J Chem Phys 141:204106
Greives, Nicholas; Zhou, Huan-Xiang (2014) Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit. Proc Natl Acad Sci U S A 111:10197-202
Pang, Xiaodong; Zhou, Huan-Xiang (2014) Distinct mechanisms of a phosphotyrosyl peptide binding to two SH2 domains. J Theor Comput Chem 13:1440003
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 (2014) Theoretical frameworks for multiscale modeling and simulation. Curr Opin Struct Biol 25:67-76
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
Qin, Sanbo; Zhou, Huan-Xiang (2013) PI(2)PE: A Suite of Web Servers for Predictions Ranging From Protein Structure to Binding Kinetics. Biophys Rev 5:41-46
Qin, Sanbo; Zhou, Huan-Xiang (2013) Using the concept of transient complex for affinity predictions in CAPRI rounds 20-27 and beyond. Proteins 81:2229-36

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