SH3-SPOT: An algorithm to predict preferred ligands to different members of the SH3 gene family

We have developed a procedure to predict the peptide binding specificity of an SH3 domain from its sequence. The procedure utilizes information extrac ted from position-specific contacts derived from six SH3/peptide or SH3/pro tein complexes of known structure. The framework of SH3/peptide contacts de fined on the structure of the complexes is used to build a residue-residue interaction database derived from ligands obtained by panning peptide libra ries displayed on filamentous phage. The SH3-specific interaction database is a multidimensional array containin g frequencies of position-specific contacts. As input, SH3-SPOT requires th e sequence of an SH3 domain and of a query decapeptide ligand. The array, t hat we call the SH3-specific matrix, is then used to evaluate the probabili ty that the peptide would bind the given SH3 domain. This procedure is fast enough to be applied to the entire protein sequence database. Panning experiments were performed to search putative specific ligands of d ifferent SH3 domains in a database of decapeptides, or in a database of pro tein sequences. The procedure ranked some of the natural partners of intera ction of a number of SH3 domains among the best ligands of the similar to 5 .6 x 10(9) different decapeptides in the SWISSPROT database. We expect the predictive power of the method to increase with the enrichment of the SH3-s pecific matrix by interaction data derived from new complex structures or f rom the characterization of new ligands. The procedure was developed using the SH3 domain family as test case but its application can easily be extend ed to other families of protein domains (such as, SH2, MHC, EH, PDZ, etc.). (C) 2000 Academic Press.