I am currently involved in modeling protein/substrate interactions. The system I am examining is the biotin/avidin and streptavidin system. In general I am using free energy perturbation methods to design molecules which bind to the protein even more efficiently than biotin. In addition, I am simulating the effect of point mutations on the binding of the substrate to the host. The mutations S27A and W79A are currently in progress. The tryptophan mutation in particular is quite significant since the binding energy of biotin to streptavidin with that particular mutation has recently been determined experimentally. Our results reproduce in a qualitative way the experimentally determined values. Further simulations will be carried out on these systems and free energy derivative information will be used to plan appropriate future mutations. In addition, recent structural work has been completed on the streptavidin/HABA (hydroxyazo-benzoic acid) system, and this is being considered as an alternative substrate to study. It is clear that each stage of the setup, and analysis of the results for this project, requires access to a visualization environment. The facilities of the UCSF Computer Graphics Laboratory fill this need very well, and I consider them essential for effective completion of these research projects.
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