A novel method for the modelling of peptide ligands to their receptors

A knowledge-based approach to the modelling of enzyme-peptide inhibitor complexes is described. Given the structure of an enzyme, and knowledge of its binding site, the method seeks to predict the binding geometry of a peptide ligand. This novel method involves using examples of side-chain packing derived from proteins of known three-dimensional structure to define possible packing arrangements of a peptide inhibitor group to its binding site. A suite of programs, GEMINI, was written and used to predict the packing of pairs of amino acid groups from three inhibitors complexed to their enzymes for which the X-ray structures were available. These included the Phe group of the inhibitor H142 bound to endothiapepsin, the Leu group of CLT complexed to thermolysin and the C-terminus of Gly-L-Tyr bound to carboxypeptidase A. A detailed comparison of the modelled and observed inhibitor coordinates was made. This approach may be extended to modelling other types of protein interactions.