研究领域
Computational Chemistry/Chemical Biology/Physical Chemistry
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. Our lab also collaborates with experimental groups on and off campus.
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 K(sub-eq)=exp(-Go/RT), which in turn is the ratio of the rate-constants for association k(sub-on) and dissociation k(sub-off). It has been shown experimentally that different molecules that bind to the same chemical receptor may have similar binding free energies (G), 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.
近期论文
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Roberts, C. C. and Chang, C-E. A.*, Modeling of Enhanced Catalysis in Multi-enzyme Nanostructures: Effect of Molecular Scaffolds, Spatial Organization, and Concentration. J. of Chemical Theory and Computation, 2015
Zhang, X., Niu, D., Carbonell, A., Wang, A., Lee, A., Tun, V., Wang, Z., Carrington, J., Chang, C.-E. A. and Jin, H., Argonaute PIWI domain and microRNA duplex structure regulate small RNA sorting in Arabidopsis. Nature Communications, 2014, in press
Protonation states of the traptophan synthase internal aldimine active site from sold-state NMR spectroscopy: direct observation of the protonated Schiff base linkage to pyridoxal-5’-phosphate. Caulkins, B.G., Bastin, B., Yang, C., Neubauer, T.J., Young, R.P., Hilario, E., Huang, Y.M., Chang, C.-E. A., Fan, L., Dunn, M.F., Marsella, M.J., Mueller, L.J., J. Am. Chem. Soc. 2014, 136, 12824-12827.
Tang, Z., Zhang, Q., Yin, Y., Chang, C.-E. A.*, Facet Selectivity of Ligands on Silver Nanoplates: Molecular Mechanics Study. J. of Physical Chemistry C, 2014, 118, 21589-21598.
Huang, Y.-M. M. Kang, M., and Chang, C.-E. A., Switches of hydrogen-bonds During Ligand-protein Association Processes as Determinants of Binding Kinetics, Journal of Molecular Recognition, 2014.27, 537-548.
Huang, Y.-M. M. and Chang, C.-E. A., Achieveing Specificity and Promiscuity by Loop Recognition: Case of the FHA domains. PLoS ONE, 2014, 9, e98291.
Axe, J. M., Yezdimer, E. M., O’Rourke, K. F., Kerstetter, N. E., You, W. Chang, C.-E. A. and Boehr, D. D. J. Am. Chem. Soc., 2014, 136, 6818-6821.
Zeng, S., Huang, Y-M. M., Chang, C-E. A.*, and Zhong, W*. Protein Binding for Detection of Small Changes on Nanoparticle Surface, Analyst, 2014, 139, 1364-1371.
Chang, C-E. A., and Huang, Y-M. M. Atomistic Modeling of Phosphopeptide Recognition of Modular Domains, Ralph A. Wheeler, editors: Annual Reports in Computational Chemistry, 2013, Vol. 9, 61-84.
Roberts, C. and Chang C-E. A., Ligand binding pathway elucidation for cryptophane host-guest complexes. J. of Chemical Theory and Computation, 2013, 9:2010-2019
Kumar, E. A., Chen, Q., Kizhake, S., Kolar, C., Kang, M., Chang, C-E. A., Borgstahl, G. E. O., and Natarajan, A., The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides. Scientific Reports, 2013, 3:1639
Yaghmaei, S., Roberts, C., Ai, R., Mizwicki, M. T., and Chang C-E. A., Aognist and antagonist binding to the nuclear vitamin D receptor, dynamics, mutation effects and functional implications. In Silico Pharmacology, 2013, 1:2
Huang, Y.-M. M., Kang, M., and Chang C-E. A., Mechanistic insights into phosphopeptide-binding BRCT domains: preorganization, flexibility and phosphate recognition. J. of Physical Chemistry B, 2012, 116,10247-10258
Ai, R., and Chang, C-E. A., Ligand-Specific Homology Modeling of Human Cannabinoid (CB1) Receptor. Journal of Molecular Graphics and Modelling. 2012
Huang, Y.M.M, Chen, W., Potter, M. P., and Chang, C-E. A., Insights from Free-Energy Calculations: Protein Conformational Equilibrium, Driving Forces, and Ligand-Binding Modes., Biophysical J., 2012, 103, 342-351
Kang, M., Roberts, C., Cheng, Y. and Chang, C-E. A., Gating and Intermolecular Interactions in Ligand-protein Association: Coarse-grained Modeling of HIV-1 Protease, J. of Chemical Theory and Computation, 2011, 10:3438-3446
Chang, C-E. A., Ai, R, Gutierres, M., Marsella, M. J., Successful biomedical applications: cannabinoid analogues for therapeutic use. Computer-Aided Drug Design, Methods in Molecular Biology, book editor: Baron, R. 2012, 819, 595-613
Huang, Y.M.M and Chang, C-E. A., Mechanism of PhosphoThreonine/Serine Recognition and Specificity for Modular Domains from All-atom Molecular Dynamics, BMC Biophysics, 2011, 4, 12-25
Lai, J., Niks, D., Wang, Y., Domratcheva, T., Barends, T. R. M., Schwarz, F., Olsen, R. A., Elliott, D. W., Fatmi, M. Q., Chang, C-E. A., Schlichting, I., Dunn, M. F. and Mueller, L. J., X-ray and NMR Crystallography in an Enzyme Active Site: The Indoline Quinonoid Intermediate in Tryptophan Synthase, J. Am. Chem. Soc., 2011, 133 (1), 4–7
Fatmi, M.Q., Chang, C.E. A. The role of oligomerization and cooperative regulation in protein function: The case of tryptophan synthase. PLos Computational Biology, 2010, 6, e1000994
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