Peptide-mediated interactions in which a short linear motif binds to a globular domain play major roles in cellular regulation. and therefore there is a need for powerful and accurate methods that are optimized for the prediction of peptide-binding sites. Here we present ligand binding site prediction based on fragment mapping (FTmap) we optimize a protocol that specifically takes into account peptide binding site characteristics. In a high-quality curated set of peptide-protein complex structures identifies for most the accurate site of peptide binding among the top ranked predictions. We anticipate that this protocol will significantly increase the quantity of accurate structural models of peptide-mediated interactions. and interactions is usually often the very step that regulates protein function 4. One of the important sources of information about interactions is the structure of a protein-protein complex. This structure can be used as a starting point for the characterization and manipulation of an conversation. As an example residues that are critical for an conversation may be recognized using experimental or computational alanine scanning of interface residues 5-8. Abolishment of an conversation LDN193189 HCl by mutation of these critical residues may help identify the functional role of this conversation 9. Finally targeting of LDN193189 HCl the interface of critical interactions by small molecules is gaining increasing importance in drug design in addition to the traditional design of inhibitors of enzyme reactions 10 11 While the quantity of experimentally solved structures is increasing the portion of protein complexes among these remains very low around 10-20% 12. This calls for the development of methods that identify a binding site on a protein structure or even better model the structure of a complex from your free monomers. Indeed the field of docking in which the structure of a complex is modeled from Rabbit polyclonal to PHF13. your structures of the free components has significantly improved over the last 2 decades (observe this CAPRI issue for some of the latest improvements). Identification of the binding site on a protein structure is a first step towards generation of an accurate structural model of an conversation. If crucial residues that mediate the binding of two partners can be recognized this has two important effects: first of all experiments can be directed towards those LDN193189 HCl residues and the functional effect of an conversation may be analyzed. Second of all docking methods may be focused on a specific interface patch 13. For instance we have previously developed a protocol that starting from a known binding site and an LDN193189 HCl approximate peptide conformation within that site can accurately model the peptide-protein complex structure (FlexPepDock 14 15 even without any detailed knowledge of the peptide structure within the binding site (FlexPepDock 16). Thus binding site identification allows to focus and to intensify the search to relevant sites rather than wasting time in a global full docking search which can also result in additional false positives. Limited methods have been proposed to identify peptide binding sites on proteins (e.g. recommendations 17-19). These use information both from your structures of the partners as well as from your sequence. PepSite identifies peptide binding sites on protein structures by searching for regions that match a spatial PSSM derived from known peptide binding protein receptor structures 17. As such it can not only identify the location of the peptide binding site but also suggests a sequence motif for the binding peptides. Consequently information about the actual peptide-binding partners is also provided. Another recently published approach uses the BRIX database of interacting fragments to predict the structure of peptide-protein complexes starting from a peptide sequence and a solved receptor structure 19. As for peptide binding sites these existing methods perform well mainly on known binding sites such as WW SH3 and kinase domains but less well on non-standard peptide-mediated interactions. Thus new tools are needed to address this problem. Here we suggest an approach based on the observation that protein functional sites including peptide binding.