MOLECULAR MODELING OF THE INTERACTION OF POLYPROLINE-BASED PEPTIDES WITH THE ABL-SH3 DOMAIN - RATIONAL MODIFICATION OF THE INTERACTION

A molecular model of the interaction of polyproline-rich peptides with the Abl-SH3 domain is proposed, based on docking calculations with th e DOCK program coupled with molecular dynamics simulations. Two distin ct binding modes of the peptide to the same aromatic-rich region (Tyr1 0, Phe12, Trp39, Trp50, Tyr55) of the domain were obtained. It is prop osed that these two models could represent different binding modes of proline-rich peptides to Src homology region 3 domains. Several peptid e mutants were designed to determine whether the two orientations were possible. Analysis of the K-d values and fluorescence emission of the se peptides indicate that one of the orientations is more plausible an d that residues at position 4 of the peptide interact with the RT loop , being important in modulating the peptide affinity for the Abl-SH3 d omain.