Dr. H. Hu　　　胡浩博士

PhD  UNC - Chapel Hill

Room 406
Chong Yuet Ming Chemistry Building
The University of Hong Kong
Pokfulam Road
Hong Kong

Enzymes play critical roles in life processes by catalyzing vastly diverse chemical reactions, ranging from simple carbon dioxide hydration to complicated long-range electron / radical transfer and photochemical process. Compared with uncatalyzed processes, enzymes can significantly speed up the reactions. Origin of the catalytic power of enzymes constitutes an intellectual challenge to our understanding of nature; the knowledge of which would immediately contribute to biomedicinal research such as drug design. Development of efficient simulation methods for accurate modeling of enzyme catalysis is our focal point, which requires research in both quantum mechanical computation methods and statistical phase-space sampling techniques.

 

Structure, dynamics, and function of proteins

Although the functions of protein molecules are ultimately determined by the primary sequences, the thermodynamics and kinetics of the functioning process are direct result of the interplay between protein structure and dynamics. A complete picture of the energy landscape of protein molecule is the key to the understanding of protein functions. We are interested in the correlation between protein structure and dynamics, in particular how this correlation was shaped by the functioning requirement in the thermodynamic evolution process. Understanding the hierarchic organization of protein function and dynamics, in both temporal and chemical spaces, is our final goal.

 

Development and application of QM and QM/MM method

Quantum mechanics is the most accurate theory for computing molecular properties. The progress for the application of QM to biomolecular system has been unsatisfactory, presumably due to the computational cost of QM calculations. We like to push the development of QM and QM/MM methods with focus on the application in biomolecular systems. A few areas that we are interested in are: linear-scaling QM methods, QM derived polarizable force fields, and efficient QM/MM methods.

 

Molecular design

This project applies aforementioned computational methods to the design of new molecules for medicinal or economic significance. The questions we like to explore are: (1) Based on the atomistic and even electronic information available for the transition state of an enzyme-catalyzed reaction, can we design new and effective inhibitors? (2) Can we design a new enzyme bottom-up from a desired reaction mechanism?

 

1. Hu, H.*, Boone, A., and Yang, W. T., (2008) Mechanism of OMP decarboxylation in orotidine 5'-monophosphate decarboxylase, J. Am. Chem. Soc., in print
2. Hu, H. and Yang, W. T. (2008) Free energies of chemical reactions in solution and in enzymes with ab initio QM/MM methods, Annu. Rev. Phys. Chem., 59:573-601
3. Zeng, X. C., Hu, H., Hu, X. Q., Cohen, A. J., and Yang, W. T. (2008) QM/MM calculation of electron transfer process with a fractional number of electrons approach, J. Chem. Phys., 128:124510
4. Hu, H., Lu, Z. Y., Parks, J. M., Burger, S. K., and Yang, W. T., (2008) Quantum mechanics / molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: Sequential sampling and optimization on the potential of mean force surface, J. Chem. Phys., 128:034105
5. Hu, H.*, Lu, Z. Y., Elstner, M., Hermans, J., and Yang, W. T., (2007) Simulating water with the SCC-DFTB method: From molecular clusters to the liquid state, J. Phys. Chem. A, 111:5685-5691
6. Hu, H., Lu, Z. Y., and Yang, W. T., (2007) Fitting molecular electrostatic potentials from quantum mechanical calculations, J. Chem. Theory Comput., 3:1004-1013 (20 most-accessed articles)
7. Hu, H., Lu, Z. Y., and Yang, W. T., (2007) QM/MM Minimum Free Energy Path: Methodology and application to triosephosphate isomerase, J. Chem. Theory Comput., 3:390-406 (20 most-accessed articles)
8. Hu, H., Hermans, J., and Lee, A. L., (2005) Relating side-chain mobility in proteins to rotameric transitions: Insights from molecular dynamics simulations and NMR, J. Biol. NMR, 32:151-162
9. Hu, H., and Yang, W., (2005) Dual-topology-dual-coordinate free energy simulation using QM/MM force field, J. Chem. Phys., 123:41102
10. Hu, H., Clarkson, M. W., Hermans, J., and Lee, A. L. (2003) Increased rigidity of eglin c at acidic pH: Evidence from NMR spin relaxation and MD simulation, Biochemistry, 42:13856-13868
11. Hu, H., Elstner, M, and Hermans, J. (2003) Comparison of a QM/MM force field and molecular mechanics force fields in simulations of alanine and glycine "dipeptides" (Ace-Ala-Nme and Ace-Gly-Nme) in water in relation to the problem of modeling the unfolded peptide backbone in solution, Proteins: Struct, Funct. & Genet., 50:451-463
12. Hu, H., Yun, R.-H., and Hermans, J. (2002) Reversibility of free energy simulations: Slow growth may have a unique advantage (With a note on the use of Ewald summation), Mol. Simulation, 28:67-80