Protein-protein docking: from interaction to interactome

Abstract

The protein-protein docking problem is one of the focal points of activity in computational biophysics and structural biology. The three-dimensional structure of a protein-protein complex, generally, is more difficult to determine experimentally than the structure of an individual protein. Adequate computational techniques to model protein interactions are important because of the growing number of known protein structures, particularly in the context of structural genomics. Docking offers tools for fundamental studies of protein interactions and provides a structural basis for drug design. Protein-protein docking is the prediction of the structure of the complex, given the structures of the individual proteins. In the heart of the docking methodology is the notion of steric and physicochemical complementarity at the protein-protein interface. Originally, mostly high-resolution, experimentally determined (primarily by x-ray crystallography) protein structures were considered for docking. However, more recently, the focus has been shifting toward lower-resolution modeled structures. Docking approaches have to deal with the conformational changes between unbound and bound structures, as well as the inaccuracies of the interacting modeled structures, often in a high-throughput mode needed for modeling of large networks of protein interactions. The growing number of docking developers is engaged in the community-wide assessments of predictive methodologies. The development of more powerful and adequate docking approaches is facilitated by rapidly expanding information and data resources, growing computational capabilities, and a deeper understanding of the fundamental principles of protein interactions.

Figure 1

The general scheme of protein docking methodology development. The scan (global search for complementarity) is performed on a simplified/coarse-grained representation of proteins (e.g., digitized on a grid, or discretized/approximated in other ways). The scan can be explicit (free) or based on similarity to known cocrystallized complexes (comparative). The refinement is supposed to bring back all or some structural resolution lost in the coarse-graining (e.g., by gradual transition from s smoothed intermolecular energy landscape to the one based on a physical force field, while tracking the position of the global minimum). The validity of the approach is determined by systematic benchmarking on representative sets of structures. To see this figure in color, go online.

Figure 2

Structures with the increasing level of inaccuracy. The model structures (cyan) are overlapped with the x-ray structure (light brown). To see this figure in color, go online.

Figure 3

Structural similarity of the binding modes versus structural similarity of the interacting proteins. The structural similarity of the binding modes is described by interaction RMSD (47). The structural similarity of the interacting proteins is described by min TM-score—the lowest of the two components protein TM-scores (62). The sharp transition to small interaction RMSD occurs at the 0.4 value of structural similarity. To see this figure in color, go online.

Figure 4

Benchmarking of template-based docking. The distribution of predicted complexes accuracies is shown relative to the cocrystallized structure. The benchmarking of PDB complexes released in 2009–2011 was based on template structures from 2008 and earlier. In 36% of the complexes, the predicted structure is close to the native (interface RMSD <5 Å). To see this figure in color, go online.

Figure 5

Structural coverage of protein interactions for five genomes with the largest number of known interactions. Complexes with the x-ray structure are in red, complexes with a sequence template are in green, and complexes for which the structure of the monomers is known are in blue—structural templates are found for ∼100% of such complexes. >1/3 of these templates are estimated to be correct (Fig. 4). To see this figure in color, go online.

Figure 6

Example of docking decoys. Matches represented by the ligand’s center of mass are shown for 1bui enzyme-substrate complex. The receptor (in green) and the ligand (in cyan) are shown in cocrystallized configuration. The native match is in yellow, 10 near-native matches are in red, and 100 nonnative matches are in blue. To see this figure in color, go online.