Essential motions and energetic contributions of individual residues in a peptide bound to an SH3 domain

We have studied protein-ligand interactions by molecular dynamics simulatio ns using software designed to exploit parallel computing architectures. The trajectories were analyzed to extract the essential motions and to estimat e the individual contributions of fragments of the ligand to overall bindin g enthalpy. Two forms of the bound ligand are compared, one with the termin i blocked by covalent derivatization, and one in the underivatized, zwitter ionic form. The ends of the peptide tend to bind more loosely in the capped form. We can observe significant motions in the bound ligand and distingui sh between motions of the peptide backbone and of the side chains. This cou ld be useful in designing ligands, which fit optimally to the binding prote in. We show that it is possible to determine the different contributions of each residue in a peptide to the enthalpy of binding. Proline is a major n et contributor to binding enthalpy, in keeping with the known propensity fo r this family of proteins to bind proline-rich peptides.