Accuracy of Protein-Protein Binding Sites in High-Throughput Template-Based Modeling

Abstract

The accuracy of protein structures, particularly their binding sites, is essential for the success of modeling protein complexes. Computationally inexpensive methodology is required for genome-wide modeling of such structures. For systematic evaluation of potential accuracy in high-throughput modeling of binding sites, a statistical analysis of target-template sequence alignments was performed for a representative set of protein complexes. For most of the complexes, alignments containing all residues of the interface were found. The full interface alignments were obtained even in the case of poor alignments where a relatively small part of the target sequence (as low as 40%) aligned to the template sequence, with a low overall alignment identity (<30%). Although such poor overall alignments might be considered inadequate for modeling of whole proteins, the alignment of the interfaces was strong enough for docking. In the set of homology models built on these alignments, one third of those ranked 1 by a simple sequence identity criteria had RMSD<5 Å, the accuracy suitable for low-resolution template free docking. Such models corresponded to multi-domain target proteins, whereas for single-domain proteins the best models had 5 Å<RMSD<10 Å, the accuracy suitable for less sensitive structure-alignment methods. Overall, ∼50% of complexes with the interfaces modeled by high-throughput techniques had accuracy suitable for meaningful docking experiments. This percentage will grow with the increasing availability of co-crystallized protein-protein complexes.

Author Summary

Protein-protein interactions play a central role in life processes at the molecular level. The structural information on these interactions is essential for our understanding of these processes and our ability to design drugs to cure diseases. Limitations of experimental techniques to determine the structure of protein-protein complexes leave the vast majority of these complexes to be determined by computational modeling. The modeling is also important for revealing the mechanisms of the complex formation. The 3D modeling of protein complexes (protein docking) relies on the structure of the individual proteins for the prediction of their assembly. Thus the structural accuracy of the individual proteins, which often are models themselves, is critical for the docking. For the docking purposes, the accuracy of the binding sites is obviously essential, whereas the accuracy of the non-binding regions is less critical. In our study, we systematically analyze the accuracy of the binding sites in protein models produced by high-throughput techniques suitable for large-scale (e.g., genome-wide) studies. The results indicate that this accuracy is adequate for the low- to medium-resolution docking of a significant part of known protein-protein complexes.