Professor Warshel's research covers a wide range of problems in modern biophysical
chemistry. He and his coworkers have pioneered several of the most effective
models for computer simulations of biological molecule. The studies of Warshel's
group include the following:
Simulations of Enzyme Catalysis and Protein Action
Our early works paved the way for quantitative theoretical studies of enzymatic
reactions. These works introduced the Hybrid - Quantum Mechanical / Molecular
Mechanics (QM/MM) method and a microscopic approach for studies of electrostatic
effects in proteins. The QM/MM and related approaches allow other scientists
to study the energetics and dynamics of enzymatic reactions. Our group continues
to push the frontiers of the field developing new approaches, studying complex
effects such as quantum tunneling and entropic effects in enzymes and exploring
the action of enzymes of special biological importance.q Simulating the Dynamics
of Photobiological Processes
The first molecular dynamics simulation of a biological process was reported
by Warshel in a 1976 study of the primary event of the vision process. Warshel's
group continues to be very active in this field, studying ultrafast reactions
such as the primary processes in the photosynthetic reaction center (where their
theoretical study was the first to elucidate the correct electron transfer mechanisms)
and the photoisomerization reaction in bacteriorhodopsin.
Simulation of Chemical Reactions in Solution
In order to understand enzymatic reactions it is crucial to have a quantitative
picture of the corresponding reference reactions in solutions. The realization
of this fact led Warshel's group to spend a major effort on studying the energetics
and dynamics of chemical processes in solution. These studies include the use
and development of various QM/MM approaches and related models for quantitative
simulations of chemical reactions in solutions.
Electrostatic Energies in Macromolecules
Our early works involved the development of the first physically consistent
models for studies of electrostatic energies in proteins. The use of these models
led to the current realization that electrostatic energies provide the best
way of correlating structure and function of biological molecules. The use of
calculations of electrostatic energies in analyzing a wide range of biological
problems is a major part of the research effort of Warshel's group. This includes
evaluation of pKa's and redox potentials of proteins, drug designs, and studies
of protein-protein interactions.
The simplified model for protein folding introduced by Levitt and Warshel is
now the method of choice in most studies of protein folding. Our recent effort
in this direction has focused on developing innovative ways of using the results
of the simplified model in the evaluation of the corrresponding free energies
of more detailed all-atom models.
|1.||Computer Simulation of Protein Folding, A. Warshel, and M. Levitt, Nature, 253, 694 (1975).
|2.|| Bicycle-Pedal Model for the First Step in the Vision Process, A. Warshel, Nature, 260, 679-683 (1976).
|3.|| Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the Carbonium Ion in the Reaction of Lysozyme, A. Warshel, and Levitt, J. Mol. Biol., 103, 227 (1976).
|4.|| Computer Modeling of Chemical Reactions in Enzymes and Solution, A. Warshel, John Wiley & Sons: New York (1989). |
|5.|| Computer Simulations of Electron Transfer Reactions in Solution and Photosynthetic Reaction Centers, A. Warshel, and W.W. Parson, Ann. Rev. Phys. Chem., 42, 279 (1991).
|6.|| Simulation of Enzyme Reactions Using Valence Bond Force Fields and Other Hybrid Quantum/Classical Approaches, J. aqvist, and A. Warshel, Chem. Rev., 93, 2523 (1993).
|7.|| How Important are Quantum Mechanical Nuclear Motions in Enzyme Catalysis?, J.-K. Hwang, and A. Warshel, J. Am. Chem. Soc., 118, 11745 (1996).
|8.|| Electrostatic Origin of the Catalytic Power of Enzymes and the Role of Preorganized Active Sites, A. Warshel, Mini Review, J. Biol. Chem., 273, 27035-27038 (1998).
|9.|| How Important are Entropic Contributions to Enzyme Catalysis?, A. Warshel, J. Villa, M. Strajbl, T.M. Glennon, Y.Y. Sham, and Z.T. Chu, Proc. Natl. Acad. Sci. USA, 27, 11800-11904 (2001).
|10.|| Dynamics of Biochemical and Biophysical Reactions: Insight from Computer Simulations, A. Warshel and W.W. Parson, Quart. Rev. Biophys., 34, 563-679 (2001).
|11.|| Computer Simulations of Enzyme Catalysis: Methods, Progress and Insights, A. Warshel, Ann. Rev. of Biophysics and Biomolecular Structure, 32, 425-443 (2003).
|12.|| Exploring the Origin of the Ion Selectivity of the KcsA Potassium Channel, A. Burykin, M. Kato and A. Warshel, Proteins: Structure, Function and Genetics, 52, 412-426 (2003).
|13.|| What Really Prevents Proton Transport Through Aquaporin? Charge Self-Energy vs. Proton Wire Proposals, A. Burykin and A. Warshel, Biophys. J., 85, 3696-3706 (2003).
|| Why Does the Ras Switch "Break" by Oncogenic Mutations? A. Shurki, A. Warshel, Proteins: Struct., Funct. Genet., 55, 1-10 (2004).
|15.|| Computer Simulations of Protein Functions: Searching for the Molecular Origin of the Replication Fidelity of DNA Polymerases, J. Florian, M.F. Goodman, and A. Warshel, Proc. Natl. Acad. Sci. USA, 102, 6819-6824 (2005).
|16.|| Electrostatic Basis of Enzyme Catalysis, A. Warshel, P. K. Sharma, M. Kato, Y. Xiang, H. Liu, and M.H.M. Olsson, Chem. Rev., 106, 3210-3235 (2006).
|17.|| Modeling Electrostatic Effects in Proteins, A. Warshel, P. K. Sharma, M. Kato, and W.W. Parson, Biochim. Biophys. Acta, 1764, 1647-1676 (2006).
|18.|| On the Relationship between Thermal Stability and Catalytic Power of Enzymes, M. Roca, H. Liu, B. Messer, and A Warshel, Biochemistry, 46, 15076-15088 (2007).
|19.|| Predicting Drug-Resistant Mutations of HIV Protease, H. Ishikita and A. Warshel, Angew. Chem. Int. Ed., 47, 697-700 (2008).