Structure-based prediction of protein-protein interactions on a genome-wide scale

Nature. 2012 Oct 25;490(7421):556-60. doi: 10.1038/nature11503. Epub 2012 Sep 30.


The genome-wide identification of pairs of interacting proteins is an important step in the elucidation of cell regulatory mechanisms. Much of our present knowledge derives from high-throughput techniques such as the yeast two-hybrid assay and affinity purification, as well as from manual curation of experiments on individual systems. A variety of computational approaches based, for example, on sequence homology, gene co-expression and phylogenetic profiles, have also been developed for the genome-wide inference of protein-protein interactions (PPIs). Yet comparative studies suggest that the development of accurate and complete repertoires of PPIs is still in its early stages. Here we show that three-dimensional structural information can be used to predict PPIs with an accuracy and coverage that are superior to predictions based on non-structural evidence. Moreover, an algorithm, termed PrePPI, which combines structural information with other functional clues, is comparable in accuracy to high-throughput experiments, yielding over 30,000 high-confidence interactions for yeast and over 300,000 for human. Experimental tests of a number of predictions demonstrate the ability of the PrePPI algorithm to identify unexpected PPIs of considerable biological interest. The surprising effectiveness of three-dimensional structural information can be attributed to the use of homology models combined with the exploitation of both close and remote geometric relationships between proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Animals
  • Bayes Theorem
  • Brain / metabolism
  • Cadherins / metabolism
  • High-Throughput Screening Assays
  • Humans
  • Matrix Attachment Region Binding Proteins / metabolism
  • Mice
  • Models, Molecular
  • PPAR gamma / metabolism
  • Phylogeny
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping / methods*
  • Protein Interaction Maps*
  • Protein Kinases / chemistry
  • Protein Kinases / metabolism
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Proteome / chemistry
  • Proteome / metabolism
  • Proteomics / methods*
  • ROC Curve
  • Reproducibility of Results
  • Saccharomyces cerevisiae / chemistry
  • Saccharomyces cerevisiae / metabolism
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Transcription Factors / metabolism


  • Cadherins
  • Matrix Attachment Region Binding Proteins
  • PPAR gamma
  • Proteins
  • Proteome
  • SATB2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors
  • Protein Kinases