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

A knowledge-based approach to the modelling of enzyme- peptideinhibitor comlexes is described. Given the structure of an enzyme,and knowledge of its bindings site, the method seeks to predictthe binding geometry of a peptide ligand. This novel methodinvolves using examples of sidechain packing derived from proteinsof known three dimensional structure to define possible packingarrangements of a peptide inhibitor group to its bindings site.Asuite of progams, GEMINI, was written and used to predict thepacking of pairs of amino acid groups from three inhibitorscomplexed to their enzymes for which the X-ray strutures wereavailable. These included the Phe group of the inhibitor H142bound to endothiapepsin, the Leu group of CLT complexed to thermolysinand the C-terminus of Gly-L-Tyr bound to carboxypeptidase A.A detailed comparison of the modelled and observed inhibitorcoordinates was made. This approach may be extended to modellingother types of protein interactions.