US-Turkey Cooperative Research: Peptide-Protein Docking and Binding Free Energy Calculation

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0002127VajdaDescription: This award is to support the collaboration of Dr. Sandor Vajda, Department of Biomedical Engineering, Boston University, Boston, Massachusetts and Dr. Ugur Sezerman, Department of Biological Sciences and Bioengineering, Sabanci University, Tuzla, Istanbul, Turkey. Their goal is to further develop and apply docking and binding free energy computations to linear molecules interacting with protein targets, with specific emphasis on complex formation between antigenic peptides and major histocompatibility complex (MHC) proteins. They plan a three-step effort: Initially, to develop free energy potentials, by essentially combining molecular mechanics with empirical solvation and entropic terms. These would be used as target functions. The potentials they would obtain are to be tested on a set of protein-peptide docked decoys. In the second step, the (validated) new potentials will be used as a target function for peptide docking. This will be performed both by site mapping and via fragment assembly docking methods. The PIs intend to achieve efficiency in the fragment-docking calculations through utilization of dynamic programming. Finally, they plan to apply this procedure and test it on the MHC type I and II proteins. The research should lead to improved computerized schemes of docking for flexible ligands. This is a difficult problem that needs solutions in order to increase our understanding of protein-protein interactions, drug development and interactions among various biological molecules.Scope: The proposal addresses an important problem in molecular modeling: docking of peptides to protein receptors and calculation of binding free energy. Both structural and energetic aspects of this problem are important. The ability to predict the structural aspects and the binding affinity of ligand-receptor interactions has important implications for molecular biophysics, as well as for the emerging area of structural bioinformatics. The principal investigator has published a number of papers on this and related topics, under current NSF funding. Prof. Sezerman has previously collaborated with Dr. Vajda. This project will promote a natural fit between the PI's group and the group of his collaborator at Sabanci University in Turkey. The areas of expertise and the resources in these two places are highly complementary. The project fits well with the objective of the Division of International Programs for encouraging mutually beneficial collaboration on research in important scientific problems.