NMR characterization and molecular dynamics simulation of protein-drug interactions
A combination of NMR 15N relaxation studies and molecular dynamics simulations are being conducted to address the structural and dynamic basis of enthalpy-entropy compensation in Src SH2 peptide binding. This work expands on calorimetric experiments conducted in Dr. Stephen F. Martin's lab at the University of Texas at Austin that tested the effects of side chain conformational constraint as a drug design strategy. Fixing the conformation of a peptide ligand is theoretically expected to improve binding affinity by decreasing the unfavorable loss of entropy upon binding. Isothermal titration calorimetry (ITC) experiments illustrated however, that unfavorable and offsetting changes to the binding enthalpy of the constrained ligands yielded an equipotent peptidomimetic inhibitor. This compensation phenomenon has been widely reported for many years in the literature, but a satisfactory understanding of its structural basis in protein systems is still lacking. A more complete understanding of this phenomenon could prove very important in future drug design efforts.
NMR is being utilized to determine the solution structures of several SH2+peptide complexes as well as characterize the internal dynamics of the protein in the context of each ligand. Molecular dynamics simiulations are being employed to further detail the fast timescale vibrational patterns and energetics of the various complexes. Through the combination of experimantal data and simulations we hope to obtain a more detailed view of the microscopic distribution of conformations accessed by the protein and how these conformations come together dynamically to define the binding thermodynamics of each SH2+peptide system.