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CABS-dock is a computational method for protein–peptide molecular docking that does not require predefinition of the binding site. The peptide is treated as fully flexible, while the protein backbone undergoes small fluctuations and, optionally, large-scale rearrangements. Here, we present a specific CABS-dock protocol that enhances the docking procedure using fragmentary information about protein–peptide contacts. The contact information is used to narrow down the search for the binding peptide pose to the proximity of the binding site. We used information on a single-chosen and randomly chosen native protein–peptide contact to validate the protocol on the peptiDB benchmark. The contact information significantly improved CABS-dock performance. The protocol has been made available as a new feature of the CABS-dock web server (at http://biocomp.chem.uw.edu.pl/CABSdock/). Short abstract CABS-dock is a tool for flexible docking of peptides to proteins. In this article, we present a protocol for CABS-dock docking driven by information about protein–peptide contact(s). Using information on individual protein–peptide contacts allows to improve the accuracy of CABS-dock docking. [ABSTRACT FROM AUTHOR]

Background: The characterization of protein-peptide interactions is a challenge for computational molecular docking. Protein-peptide docking tools face at least two major difficulties: (1) efficient sampling of large-scale conformational changes induced by binding and (2) selection of the best models from a large set of predicted structures. In this paper, we merge an efficient sampling technique with external information about side-chain contacts to sample and select the best possible models.Methods: In this paper we test a new protocol that uses information about side-chain contacts in CABS-dock protein-peptide docking. As shown in our recent studies, CABS-dock enables efficient modeling of large-scale conformational changes without knowledge about the binding site. However, the resulting set of binding sites and poses is in many cases highly diverse and difficult to score.Results: As we demonstrate here, information about a single side-chain contact can significantly improve the prediction accuracy. Importantly, the imposed constraints for side-chain contacts are quite soft. Therefore, the developed protocol does not require precise contact information and ensures large-scale peptide flexibility in the broad contact area.Conclusions: The demonstrated protocol provides the extension of the CABS-dock method that can be practically used in the structure prediction of protein-peptide complexes guided by the knowledge of the binding interface. [ABSTRACT FROM AUTHOR]

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 extensively 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 receptors (available as a server at http://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 interaction model.Conclusions: The results show that the CABS-dock method may be useful as the primary docking tool in specific protein-protein docking cases similar to EphB4-EphrinB2 complex-that is, where a short linear motif fragment can be identified. [ABSTRACT FROM AUTHOR]

Protein–peptide interactions play essential functional roles in living organisms and their structural characterization is a hot subject of current experimental and theoretical research. Computational modeling of the structure of protein–peptide interactions is usually divided into two stages: prediction of the binding site at a protein receptor surface, and then docking (and modeling) the peptide structure into the known binding site. This paper presents a comprehensive CABS-dock method for the simultaneous search of binding sites and flexible protein–peptide docking, available as a user’s friendly web server. We present example CABS-dock results obtained in the default CABS-dock mode and using its advanced options that enable the user to increase the range of flexibility for chosen receptor fragments or to exclude user-selected binding modes from docking search. Furthermore, we demonstrate a strategy to improve CABS-dock performance by assessing the quality of models with classical molecular dynamics. Finally, we discuss the promising extensions and applications of the CABS-dock method and provide a tutorial appendix for the convenient analysis and visualization of CABS-dock results. The CABS-dock web server is freely available at http://biocomp.chem.uw.edu.pl/CABSdock/ . [ABSTRACT FROM AUTHOR]