The computational effort of my research group currently focus on determination of the structure, specificity, and function of hemoproteins, particularly cytochrome P450 monooxygenases, nitric oxide synthases, lactoperoxidase, and proteins such as myoglobin. Previous efforts have concentrated on the use of DOCK to try to predict the substrate specificity of cytochrome P450 enzymes for which crystal structures are available. This effort is being extended to enzymes other than cytochrome P450cam and to a wider variety of substrate classes. In order to extend this work to the enzymes of greatest interest, it is necessary to construct models of the P450 enzyme for which crystal structures have not been determined. Model building is also being used to direct site specific mutagenesis work on lactoperoxidase. In the peroxidase area, we are carrying out site specific mutagenesis studies to determine the relationship between structure and function. These correlations are desired for their intrinsic importance but are also to be used to prepare hemoprotein catalysts with novel and unique functions and specificities. For this project, we primarily use the graphics capability of the CGL but plan in the future to apply some of the predictive methodology being developed for the P450 enzymes to the peroxidases. A further line of computation-dependent research in my laboratory is an effort to develop structure-based inhibitors of the Kaposi sarcoma protease, the Mycobacterium tuberculosis alkylhydroperoxidase (ahpC) and, in collaboration with C. C. Wang, several targets in the parasitology area. The purpose of these studies is to develop methodologies and to apply them to the search for potent inhibitors of the target proteins.
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