Modeling EphB4-EphrinB2 protein–protein interaction using flexible docking of a short linear motif

Background: Many protein–protein interactions are mediated by a short linear motif. Usually, amino acid sequences of those motifs are known or can be predicted. It is much harder to experimentally characterize or predict their structure in the bound form. In this work, we test a possibility of using flexible docking of a short linear motif to predict the interaction interface of the EphB4-EphrinB2 complex (a system exten- sively studied for its significance in tumor progression) .Methods: In the modeling, we only use knowledge about the motif sequence and experimental structures of EphB4-EphrinB2 complex partners. The proposed protocol enables efficient modeling of significant conformational changes in the short linear motif fragment during molecular docking simulation. For the docking simulations, we use the CABS-dock method for docking fully flexible peptides to flexible protein recep- tors (available as a server at ://biocomp.chem.uw.edu.pl/CABSdock/). Based on the docking result, the protein–protein complex is reconstructed and refined.Results: Using this novel protocol, we obtained an accurate EphB4-EphrinB2 interac-tion model. Conclusions: The results show that the CABS-dock method may be useful as the pri- mary docking tool in specific protein–protein docking cases similar to EphB4-EphrinB2 complex—that is, where a short linear motif fragment can be identified.