Peptide-mediated interactions are gaining increased attention due to their predominant roles in the many regulatory processes that involve dynamic interactions between proteins. The structures of such interactions provide an excellent starting point for their characterization and manipulation, and can provide leads for targeted inhibitor design. The relatively few experimentally determined structures of peptide-protein complexes can be complemented with an outburst of modeling approaches that have been introduced in recent years, with increasing accuracy and applicability to ever more systems. We review different methods to address the considerable challenges in modeling the binding of a short yet highly flexible peptide to its partner. These methods apply an array of sampling strategies and draw from a recent amassing of knowledge about the biophysical nature of peptide-protein interactions. We elaborate on applications of these structure-based approaches and in particular on the characterization of peptide binding specificity to different peptide-binding domains and enzymes. Such applications can identify new biological targets and thus complement our current view of protein-protein interactions in living organisms. Accurate peptide-protein docking is of particular importance in the light of increased appreciation of the crucial functional roles of disordered regions and the many linear binding motifs embedded within.
Bibliographical noteFunding Information:
This work was funded by the Israel Science Foundation , founded by the Israel Academy of Science and Humanities (grant number 319/11 ), the USA-Israel Binational Science Foundation (grant number 2009418 ), and by the European Research Council under the ERC Grant Agreement #310873 to OSF. NL was supported by an EMBO long-term fellowship (ALTF 1121-2011). We thank Edward Dubrovsky, John Karanicolas, and Chu Wang for supplying model coordinates for Figure 1 .