The University of Notre Dame is awarded a grant to pursue grid-enabled integration of experimental data and simulations for flexible protein docking. The elucidation of interactions of a protein with ligands or other proteins is crucial for structure-based drug design and proteomics. Modeling the flexibility of proteins is substantially more accurate (and more expensive) than considering the protein as a rigid conformation. Current methodology effectively accommodates side chain motions. In this award this methodology is extended to accommodate larger motions using experimental data and multiscale simulations. The efficiency of docking will also be improved through integration of docking protocols with conformational sampling and analysis. These methods will be validated on HIV-1 protease, HIV-1 integrase, and Dihydrofolate Reductase (DHFR), for which abundant structural and dynamical data exists. Putative interactions will be validated through NMR experiments. This research will produce grid-based tools and a database for molecular simulations and docking accessible to the research community. A novel aspect of the database technology will be the efficient management of reliability and availability of storage on the grid. There will be interdisciplinary training and collaboration among students and the investigators.
