This proposal will fund the training of post-doctoral researcher Jeffrey J. Gray in the laboratory of Professor David Baker in the Department of Biochemistry at the University of Washington. Gray will be a Ph.D. chemical engineer in August of 2000, and he is an expert in scientific computation and colloid science including self-assembly processes and electrostatics. The goal of the training period is to make Gray an expert in genomics and protein biophysics. Gray's ultimate career goal is to lead an independent research group which will conduct fundamental research at the interface of biology and engineering. In addition to genomics and protein interests, Gray's long-term research interests include biomaterials, drug design, and nanotechnology. Gray's training will consist of courses, lab work in David Baker and Stan Fields' laboratories, and a research project in functional protein genomics. Baker's laboratory is one of the leaders in protein characterization, structure determination, and computational structure prediction. Stan Fields is one of the leaders in experimental protein genomics, having pioneered the two-hybrid technique. The goal of the research project is to develop a tool to predict the structure of protein-protein complexes given structures of the isolated proteins. This tool will be useful for rapid and inexpensive genomic level studies of protein interactions. In the long term, this will be useful in mapping genetic data to molecular level function. In addition, the work will necessarily improve understanding of molecular potentials, solvation phenomena, and macromolecular thermodynamics. . Besides these fundamental scientific issues, the knowledge of protein-protein interactions developed may have significant impact for protein-related diseases and drug design. The project will draw from Gray's expertise in electrostatics, and protein electrostatics will be modeled using the efficient and accurate generalized Born model. For tool validation, Gray will first search for correct docked structures starting with perturbed bound structures or individual protein structures in their docked configurations. Subsequently, the tool will be generalized to include side-chain and main chain flexibility to be able to model docking beginning with undocked protein structures. Finally, genomic level analyses will be made to compliment experimental two-hybrid studies of protein-protein interactions.
