A NOVEL COMPUTER MODELING APPROACH TO THE STRUCTURES OF SMALL BIOACTIVE PEPTIDES - THE STRUCTURE OF GONADOTROPIN-RELEASING-HORMONE

A novel computer modeling approach suitable for the structure analysis of small bioactive peptides has been developed. This approach involve s identification of conformational patterns in protein structure data bank based on the sequence homology with the bioactive peptide. The mo dels built on the basis of this homology and having common conformatio nal patterns are analyzed under the structural constraints derived fro m the activity data of various synthetic analogs of the peptide. Appli cation of this procedure to the gonadotropin-releasing hormone (GnRH) resulted in a library of possible structures for GnRH, 9 among which s hared a common beta-turn. Further analysis of the structures containin g the beta-turn motif, in the context of the structure-activity data, led to a model for the active conformation of GnRH. The topology of th e putative receptor binding site of the hormone is defined by a contig uous surface formed through an appropriate juxtaposition of the N-term inal pGlu1, the guanidyl group of Are, aromatic side chain of Trp3, an d the Gly10-NH2 at the C-terminal end.