Two lines of research currently under way in my laboratory require computational efforts. The first of these focuses on the structure, specificity, and function of hemoproteins, particularly cytochrome P450 monooxygenases, peroxidases, and proteins such as myoglobin. In the cytochrome P450 area, we are attempting to determine whether the specificities of the enzymes for which crystal structures are available can be predicted using DOCK and molecular dynamics calculations. Studies under way show that DOCK provides reasonable first estimates of potential substrates for cytochrome P450cam. Collaborative studies with Dr. Gilda Loew, Molecular Research Institute, Palo Alto, using molecular dynamics calculations have been found to predict the absolute stereochemistry of simple oxidations catalyzed by the same cytochrome P450 enzyme. Although Dr. Loew carries out most of the calculations, we require some capability to test her results at UCSF. Finally, we are developing a chemical method for the analysis of active site topology and require the graphics capabilities of the Computer Graphics Laboratory to validate the method by comparing the predicted results with the actual structures of the three enzymes for which crystal structures exist. 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 w ith novel and unique functions and specificities. For this project we currently 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. The second line of computation-dependent research in my laboratory is the effort to develop structure-based inhibitors of a variety of AIDS related proteins, including the HIV protease and, more recently, the Mycobacterium tuberculosis ahpC protein. This work is carried out in collaboration with Peter Kollman and Tack Kuntz, but some of the work, particularly energy calculations of inhibitor fit and DOCK analyses, are currently carried out by my laboratory. 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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