2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions

Abstract

Protein-protein interactions are considered as one of the next generation of therapeutic targets. Specific tools thus need to be developed to tackle this challenging chemical space. In an effort to derive some common principles from recent successes, we have built 2P2Idb (freely accessible at http://2p2idb.cnrs-mrs.fr), a hand-curated structural database dedicated to protein-protein interactions with known orthosteric modulators. It includes all interactions for which both the protein-protein and protein-ligand complexes have been structurally characterized. A web server provides links to related sites of interest, binding affinity data, pre-calculated structural information about protein-protein interfaces and 3D interactive views through java applets. Comparison of interfaces in 2P2Idb to those of representative datasets of heterodimeric complexes has led to the identification of geometrical parameters and residue properties to assess the druggability of protein-protein complexes. A tool is proposed to calculate a series of biophysical and geometrical parameters that characterize protein-protein interfaces. A large range of descriptors are computed including, buried accessible surface area, gap volume, non-bonded contacts, hydrogen-bonds, atom and residue composition, number of segments and secondary structure contribution. All together the 2P2I database represents a structural source of information for scientists from academic institutions or pharmaceutical industries.

Figure 1.

The 2P2I website and its main features. (A) 2P2Idb is a hand-curated database dedicated to the inhibition of protein–protein complexes with orthosteric modulators. It displays structural information about protein–protein, protein–ligand complexes and small molecule inhibitors. For each of the 14 families, sub-divided into two classes (protein–peptide and protein–protein), clickable html pages are provided with pre-calculated interface parameters, binding affinity data and links to related sites of interest (UniProt, PubMed, PDBsum, PDBe and ChemSpider). Protein–protein and protein–ligand complexes can be interactively visualized using Jmol applets and user-friendly menus. (B) 2P2Iinspector is a tool to analyse protein–protein interfaces in terms of geometric and physico-chemical descriptors. A total of 60 descriptors are computed including, buried accessible surface area, gap volume, non-bonded contacts, hydrogen-bonds, atom and residue composition, number of segments and secondary structure contribution. Users can analyze protein complexes from the PDB using standard four letter accession codes or upload their own files. (C) 2P2Iscore is a tool to assess the druggability of protein–protein interfaces. Comparison of protein–protein interfaces in 2P2Idb with standard heterodimers has allowed us to define six interface parameters to characterize protein–protein interfaces with a known modulator. Users are invited to compute five parameters using the 2P2Iinspector tool. The interfacial pocket volume should be calculated with Q-SiteFinder (http://www.modelling.leeds.ac.uk/qsitefinder). A color-coded table is provided to compare user defined parameters to those in 2P2Idb. A qualitative score is given for the six key parameters to assess the druggability of the interface. Detailed help documentation is available as PDF files for the different features.