DINC 2.0: A New Protein-Peptide Docking Webserver Using an Incremental Approach

Abstract

Molecular docking is a standard computational approach to predict binding modes of protein-ligand complexes by exploring alternative orientations and conformations of the ligand (i.e., by exploring ligand flexibility). Docking tools are largely used for virtual screening of small drug-like molecules, but their accuracy and efficiency greatly decays for ligands with more than 10 flexible bonds. This prevents a broader use of these tools to dock larger ligands, such as peptides, which are molecules of growing interest in cancer research. To overcome this limitation, our group has previously proposed a meta-docking strategy, called DINC, to predict binding modes of large ligands. By incrementally docking overlapping fragments of a ligand, DINC allowed predicting binding modes of peptide-based inhibitors of transcription factors involved in cancer. Here, we describe DINC 2.0, a revamped version of the DINC webserver with enhanced capabilities and a more user-friendly interface. DINC 2.0 allows docking ligands that were previously too challenging for DINC, such as peptides with more than 25 flexible bonds. The webserver is freely accessible at http://dinc.kavrakilab.org, together with additional documentation and video tutorials. Our team will provide continuous support for this tool and is working on extending its applicability to other challenging fields, such as personalized immunotherapy against cancer. Cancer Res; 77(21); e55-57. ©2017 AACR.

Figure 1. Incremental docking of a modified peptide

The proto-oncogene tyrosine protein kinase Src (c-Src) has been associated with breast cancer and osteoporosis [11]. A known peptidomimetic inhibitor, capable of binding to the Src SH2 domain, has 77 atoms and 17 DoFs. This modified peptide provides a good example of the use of DINC’s incremental approach for binding mode prediction. DINC starts by selecting a small fragment of the ligand (top left), with only 6 DoFs (depicted in green), and using it as input for the first round of docking to the SH2 domain (depicted in grey). The best binding modes are selected across multiple parallel docking runs, and the corresponding fragments are expanded by adding a small number of atoms. These extended fragments are used as input for the second round of docking, in which a new subset of 6 flexible DoFs is explored. These flexible DoFs involve some of the “new” atoms (red) and some of the “old” atoms (blue), as depicted in the best binding mode obtained in round 2 (top right). This process continues until the entire ligand has been reconstructed (bottom left and right). In this example, the root mean square deviation (RMSD) between the obtained model and the corresponding crystal structure of the same complex (PDB code 1SKJ) is only 1.97 Å.