This project presents a multiscale computational investigation of mechanisms of recognition of novel peptide and small-molecule based therapeutics for targeting cell surface receptors at allosteric sites. The research program builds on the unifying theme of my laboratory and my long-standing effort to integrate multiscale approaches of computational molecular biophysics with data from various experimental techniques to provide a unique methodology for probing ligand/receptor systems of pharmacological significance. Specifically, we will study receptors and ligands of the tyrosine kinase family and signaling proteins of the G-protein coupled receptor family. The proposed studies involve a host of computational approaches (docking, conformational sampling, free-energy methods) to understand the folding of mimetic peptides and binding of insulinanalogues to its receptor as well as for understanding mechanisms by which small-molecules can allosterically block protein-protein interactions. These multiscale computational approaches are integrated with biophysical, biochemical, functional, and structural data for a holistic understanding of systems proposed. Characterizing these interactions will provide the mechanistic basis of function of these ligands and receptors needed to develop novel inhibitory approaches.
