In the computational investigations of enzyme mechanisms, we intend to use state-of-the-art quantum chemistry methods to characterize the reaction pathways of enzyme- catalyzed reactions. This will be accomplished by: 1) defining a prototype system that contains the minimum reaction components (substrates plus active site residues) that are consistent with a proposed enzymatic mechanism; 2) developing an accurate quantum mechanical description of the prototype; 3) evaluating the effect of nearby amino acid residues and discrete water molecules on the energetics of extrema along the reaction coordinate: 4) redetermining minima and transition states along the reaction coordinate in the presence of important residues and discrete solvent using effective fragment potentials; 5) adding more protein and bulk solvent and recalculating energies along the reaction coordinate. A special version of the GAMESS computational chemistry package, developed in collaboration with the group of Mark Gordon at Iowa State University, will be used to perform most of the computations described above. Three-dimensional protein structures form X-ray crystallography and NMR spectroscopy will be used to impose necessary geometric constraints based on the positions of perturbing amino acid residues and, in some cases, the locations of discrete water molecules.
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