TARGETING PROTEIN INTERACTIONS AND DESIGNING CHIMERIC PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are critically evaluating virtual screening protocols targeting protein/protein interfaces and developing methods to improve the speed and accuracy of molecular docking. In particular, one focus is the development of systematic search algorithms. Most conformational search methods used in molecular docking are derived from genetic or Monte Carlo algorithms1,2 tightly coupled with an energy estimate to determine Boltzmann-weighted selection. These stochastic methods do not comprehensively search conformational space, and can miss evaluating critical low-energy poses. Systematic search exhaustively samples a ligands conformation, rotational, and translational degrees of freedom with respect to the receptor. The use of systematic search methods has historically been avoided due to the computational explosion required for sampling conformational degrees of freedom. We have developed a method SKATE that analytically samples only the relevant docked space of the ligand to minimize the computational complexity. Future development will focus on further algorithmic and code optimization to enhance the functionality of systematic search in docking.In addition REMD is being used to estimate enhanced stability in chimeric proteins with semi-rigid secondary structure mimetics.