The central goal of our work is to understand the fundamental mechanism of biomolecular recognition and binding kinetics using theory and classical mechanical models. Our research involves the development and application of computational methods and theoretical models to address medically and chemically important problems. These methods are of practical importance in studying biomolecular function, and in the design of new molecules that bind strongly to their receptors. Systems of particular interest include existing or potential drug targets, cell signaling complexes and chemical host-guest systems.

Multiscale modeling of biomolecular systems: Computer modeling is becoming increasingly valuable for understanding protein function and ligand-receptor interactions. Atomistic molecular dynamics, coarse-grained Brownian dynamics and continuum simulations are combined to study detailed molecular interactions, large scale protein motions, bio-molecular dynamics, and complex biochemical network. We continue developing new methods, as well as applying them to various problems, e.g. binding pathways of ligands to HIV-1 protease, assembly and motions of acetylcholinesterase tetramer, and functions of signaling and multifunctional protein complexes.

Kinetics of binding: The association of two free molecules to form a complex is one of the most important processes in chemical and biological systems. The binding affinity, or the standard free energy change of binding, is simply an alternative way of expressing its equilibrium constant Keq=exp(-DGo /RT), which in turn is the ratio of the rate-constants for association (kon) and dissociation (koff). It has been shown experimentally that different molecules that bind to the same chemical receptor may have similar binding free energies (DG), but very different binding kinetics (kon, koff). It is unclear why their kinetic features are very different. Therefore, our lab studies not only equilibrium properties, such as the free energy of binding, but also the kinetics of binding. Since basic research, e.g. computational methodology and theories, is needed in this field, we start from tractable simplified models, and then move to more complicated chemical systems and biomedically relevant systems.

Computer-aided ligand/receptor design and discovery: In drug design and discovery, finding a small molecule that maximizes binding free energy is very important and is an interesting challenge. A thorough understanding of driving forces, binding penalties, and conformational changes induced by ligand binding, should enable more accurate prediction of binding affinities. Our lab assembles state of the art methods, e.g. docking and scoring, and applies our work described above to improve the ligand-design work.

Selected Publications

Chang C-E. A., McLaughlin W. A., Baron R., Wang W., and J. Andrew McCammon J.A., Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association. Proc. Natl. Acad. Sci. U. S. A., 2008, 105: 7456-7461

Yuhui Cheng, Chang C-E. A., Yu Z., Zhang Y., Leyhk T. S., Holst M. J. and McCammon J. A., Substrate Channeling in the Sulfate Activating Complex: Combined Continuum Modeling and Coarse-grained Brownian Dynamics Studies. Biophysical J, 2008.

Gorfe, A. A., Chang, C-E. A., Ivanov I and McCammon J. A., Dynamics of the Acetylcholinesterase Tetramer. Biophysical J. 2008, 94: 1144-1154.

Chang C-E. A., Trylska J., Tozzini T. and McCammon J. A., Towards Understanding the Binding Pathways of Ligand to HIV-1 Protease, Chemical Biology and Drug Design., 2007, 1: 5-13.

Chang, C-E. A., Chen, W. and Gilson, M. K., Analysis of the Change in Ligand Entropy upon Protein Binding. Proc. Natl. Acad. Sci. U. S. A., 2007, 104: 1534-1539.

Tozzini T., Trylska J., Chang C-E. A. and McCammon J. A., A Coarse-Grained Model for the Dynamics of Flap Opening in HIV-1 Protease. J. of Structural Biology, 2007, 157: 606-615.

Tozzini T., Trylska J., Chang C-E. A.., and McCammon J. A. Coarse-grained molecular dynamics study of HIV-1 protease substrate capture and product release, Biophysical J. 2007, 92: 4179-4187.

Chen, W., Chang, C-E. and Gilson, M. K., Concepts in Receptor Optimization: Targeting the Peptide RGD . J. Am. Chem. Soc, 2006, 128: 4675-4687.

Minh, D.L., Chang, C-E, Trylska J., Tozzini T. and McCammon J. A., Macromolecular Crowding Influences on HIV-1 Protease Internal Dynamics. J. Am. Chem. Soc, 2006, 128: 6006-6007.

Chang C-E., Shen T., Trylska J., Tozzini T. and McCammon J. A., Gated Binding of Ligands to HIV-1 Protease: Brownian Dynamics Simulations in a Coarse-Grained Mode. Biophysical J, 2006, 90: 3880-3885.

Minh, D.L., Bui, J.M., Chang, C-E., Jain T., and McCammon J.A., The Entropic Cost of Protein-Protein Association: A Case Study on Acetylcholinesterase Binding to Fasciculin-2. Biophysical J, 2005, 89:L25-L27.

Chang, C-E., Chen, W. and Gilson, M. K., Evaluating the accuracy of the quasiharmonic approximation. J. of Chemical Theory and Computation, 2005, 1, 1017-1028.

Chen, W., Chang, C-E. and Gilson, M. K., Calculation of Cyclodextrin Binding Affinities: Energy, Entropy, and Implications for Drug Design. Biophysical J, 2004, 87, 3035-3049.

Chang, C-E. and Gilson, M. K., Free Energy, Entropy, and Induced Fit in Host-Guest Recognition. J. Am. Chem. Soc. 2004, 126, 13156–13164.

Chang, C.-E*., DeJong, E. S.*, Gilson, M. K., Marino, J. P., Proflavine Acts as a Rev Inhibitor by Targeting the High-Affinity Rev Binding Site of the Rev-Responsive Element of HIV-1, Biochemistry, 2003. 42, 8035-8046. (* co-first authors)

Chang, C.-E., Potter, M. J. and Gilson, M. K., Direct Calculation of Conformational Free Energies in All Degrees of Freedom, J. Phys. Chem. B., 2003. 107, 1048-1055.

Chang, C.-E and Gilson, M. K., Tork: A Conformational Analysis Method for Molecules and Complexes, J. of Comput Chem, 2003, 24, 1987-1998.