Computational Biology PhD student Ashley Conard won the RCSB PDB Poster Prize for her poster titled: “Determining the winning SH3 coalition: how cooperative game theory reveals the importance of domain residues in peptide binding” at the ISMB/ECCB 2015 conference.

Cell signaling relies on protein-protein and protein-peptide interactions involving signaling domains, which typically recognize specific peptide motifs. For instance, SH3 domains bind preferably to proline-rich amino-acid motifs. Phage-display experiments allow one to determine those motifs and whether surface or core domain mutants gain or lose preference for peptide motifs. Here, we present an approach utilizing the Shapley Value (SV) from Cooperative Game Theory to determine the importance of seven residues in the Fyn SH3’s hydrophobic core. The core positions and the residues in those positions represent the players of a cooperative game in which the worth of each coalition is measured through its capacity to discriminate the binding and non-binding mutants for certain classes of peptides. The players (positions or residues) can be seen as the features of SH3 mutants in a binary classification task. Essentially, we use a feature selection method based on the SV to assign a pay-off to each core position and residue. We quantify their importance to promote peptide binding as well as their joint effects, and their interactions, represented through networks. Our results provide novel insights suggesting that the Fyn SH3 domain must contain different signatures of amino acids to promote binding to various peptide classes. This analysis highlights residue importance for proper domain function, which helps scale conservation profiles (e.g. WebLogo) by adding functionally relevant properties. These detailed pieces of information contribute an effective and novel approach to understanding the role core residues play, next to normally investigated binding-site residues, in binding specific peptides.

The prize committee consisted of variety of specialists, the majority of which were in macromolecular crystallography. The committee reviewed posters presented at several meetings this year including the ACA, ECM, AsCA, ICSG and ISMB and chose Ashley’s for the 2015 prize. Congratulations Ashley!