Low-resolution structural modeling of protein interactome

Abstract

Structural characterization of protein-protein interactions across the broad spectrum of scales is key to our understanding of life at the molecular level. Low-resolution approach to protein interactions is needed for modeling large interaction networks, given the significant level of uncertainties in large biomolecular systems and the high-throughput nature of the task. Since only a fraction of protein structures in interactome are determined experimentally, protein docking approaches are increasingly focusing on modeled proteins. Current rapid advancement of template-based modeling of protein-protein complexes is following a long standing trend in structure prediction of individual proteins. Protein-protein templates are already available for almost all interactions of structurally characterized proteins, and about one third of such templates are likely correct.

Figure 1

Examples of simulated models. The X-ray structure is shown for comparison, with the binding site in gray.

Figure 2

Template-based docking by structural alignment.

Figure 3

Structural modeling of interactome. The flowchart shows modeling of two proteins (blue and green) interaction (orange) from the PPI network, through determination of their individual structures (X-ray structure from PDB or modeling), and the structure of their complex (X-ray structure from PDB or modeling by template-based or free docking).

Figure 4

Structural coverage of PPI in five genomes with the largest number of known protein interactions. Complexes with the X-ray structure are in red, and complexes with a sequence template are in green. Complexes for which the structure of the monomers is known or can be built by homology are in blue — structural templates are available for 99% of such complexes