Molecular Simulation

Understanding the molecular origin of enzyme catalysis is one of the most fundamental problems in molecular biology. The effects of enzymes on the reacting substrates involve varied and complicated energy contributions which depend on the structure of the enzyme-substrate complex. Thus to have a quantitative structure-function relationship is not a trivial matter. In principle, one would like to carry out ab initio quantum mechanical calculations for biomolecules. Unfortunately, such an approach cannot be implemented at present in studies of proteins.

One must therefore resort to some approximations and represent a large part of the system classically. The enzymatic reactions are described by the empirical valence bond (EVB) method, which is probably one of the most practical and consistent approaches for treating chemical reactions both in enzymes and in solution. The basic idea is to represent the overall reaction in terms of various valence bond structures and then to obtain the actual ground state by mixing these structures. The EVB potential surface is calibrated by using accurate gas-phase data or by using experimental information for the corresponding reactions in solution.

In combination with the free energy perturbation (FEP) method, the EVB-FEP method offers a convenient way to calculate the free energy profile for the enzymatic reactions. We have carried out many EVB-FEP calculations on enzymes such as serine proteinases, aspartate aminotransferase and human carbonic anhydrase I. Recently, we have proposed the quantized classical path (QCP) approach which incorporates the Feynman's path integral into the EVB framework, and offers a convenient way to obtain quantum-mechanical corrections to the rate constants of proton transfer (PT) and hydride transfer reactions in enzymes and in solution. Efforts are also invested in combining the semi-empirical quantum mechanical method such as AM1 with the EVB- FEP approach.

Molecular Simulation

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