Research
Interests
Our
research involves the development and applications of computational
methods to study biomolecular structure, dynamics, and function and
to aid the design of bioactive compounds. Methods that we have been
developing/using include molecular dynamics that simulates biomolecular
motion by solving Newtons equation of motion, Brownian dynamics that
simulates molecular motion and the diffusional encounter among biomolecules,
Feynmann path integral method that accounts for quantum nuclear tunneling
effects in simulating conformational fluctuations, sensitivity analysis
that helps to identify the determinants of biomolecular properties
and to aid molecular design, continuum-electrostatics models that
predict the electrostatic properties of biomolecules, and quantum
chemical methods that calculate the energetic, conformational and
spectroscopic properties of molecules of biological interests. In
addition, we have developed a helix-coil transition theory using
database-derived potentials to predict the helical forming propensity
of amino acid sequences. Recently, we are also interested in developing
a full quantum-mechanical treatment of protein-ligand interactions.
The biological
systems that we recently focus on are protein kinases and phosphatases.
We are interested in using the above techniques to decipher
the enzymatic mechanisms of these proteins. In addition, we
have been using a combination of computational tools to aid
the design of drugs targeting these proteins to treat diseases
such as cancer and diabetes. With the rapid advance of computer
hardware and new developments in molecular modeling and simulation
software, computational tools are becoming increasingly powerful
in computer-aided drug design. Although there is still substantial
room for further improving these techniques, the use of a combination
of methods that are based upon different approximations can
already yield useful predictions. For example, when several
methods point to the same conclusion, there is a good chance
that the conclusion is valid. Also, it is a useful strategy
to employ a hierarchical approach to computer-aided drug design
in which simpler but faster methods are first used to examine
a large number of real or virtual compounds and more sophisticated
but slower methods are then used to further evaluate a smaller
number of compounds that warrant further exploration. We have
been constructing components of such a hierarchical approach
by using existing methodologies as well as methods developed
in our own laboratory. In addition, as whole genome data are
becoming available, we are also performing large scale comparative
analyses to take selectivity into account in designing drugs
that have fewer side effects.
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| Selected
Publications
Z. Huang,
C.F. Wong and R. Wheeler, "Flexible Protein-Flexible Ligand
Docking with Disrupted Velocity Simulated Annealing",
Proteins: Structure, Function, Bioinformatics, 2008, 71, 440.
"Flexible ligand-flexible protein docking in
protein kinase systems", C. F. Wong, Biochimica et Biophysica Acta,
Proteins and Proteomics, 2008, 1784, 244
"A Mining-Minima Approach to Exploring
the Docking Pathways of p-Nitrocatechol Sulfate to YopH",
Z. Huang
and C.F. Wong, Biophys. J., 2007, 93, 4141
"Efficient Quantum Mechanical
Calculation of Solvation Free Energies Based on Density Functional
Theory, Numerical Atomic Orbitals and Poisson-Boltzmann Equation", M. Wang,
C. F. Wong, J. Liu and P. Zhang, Chem.
Phys. Lett., 2007, 442, 464.
"Rank-ordering Protein-Ligand Binding
Affinity by a QM/MM/PBSA Model", M.
Wang and C. F. Wong, J. Chem. Phys., 2007, 126,
026101.
"Calculation of Solvation Free Energy
from Quantum Mechanical Charge Density and Continuum Dielectric
Theory", M.
Wang and C. F. Wong, J. Phys. Chem. A 2006, 110,
4873
"Molecular Dynamics Simulation of Laser
Desorption of a Fragment of Protein Kinase A from Two MALDI
Matrices", C. Wang
and C. F. Wong, J. Phys. Chem. A 2006, 110,
5355
"Molecular
docking of balanol to dynamics snapshots of protein kinase
A", C.
F. Wong, J. Kua, Y. Zhang, T. P. Straatsma and A. J. McCammon, Proteins: Structure, Function and Bioinformatics 2005, 61,
850 .
"Direct estimation of entropy loss
due to reduced translational and rotational motions upon molecular
binding", B.
Lu and C. F. Wong, Biopolymers 2005, 79, 277
"Relative
contributions of desolvation, inter- and intramolecular interactions
to binding affinity in protein kinase systems", P.
A. Sims, C. F. Wong, D. Vuga, A. J. McCammon and B. M Sefton, J. Comput. Chem. 2005, 26, 668.
"Release of ADP from
the catalytic subunit of protein kinase A: A molecular dynamics
simulation study", B. Lu, C. F. Wong and A. J. McCammon, Protrein Science 2005, 14,
159
"Finite Concentration Effects
on Diffusion-controlled Reactions", S. Senapati, C.F. Wong and J.A. McCammon, J. Chem. Phys. 2004, 121 7896
"Release
of ADP from the Catalytic Subunit of Protein Kinase A: A Molecular
Dynamics Simulation Study", B.Z. Lu, C.F. Wong & J.A.
McCammon, Protein
Sci. 2004, 14, 159
"Charge Optimization of the Interface between Protein Kinases and their Ligands", P. Sims, C.F. Wong and J.A. McCammon, J. Comput.
Chem., 2004. 25, 1416
"Computational analysis of the interactions between the angiogenesis inhibitor PD173074 and fibroblast growth factor receptor ", K. Tondel, C. F. Wong and J. A. Mccammon, Journal of Theoretical & Computational Chemistry, 2003, 2, 43
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