Inferring interaction partners from protein sequences

Anne Florence Bitbol, Robert S. Dwyer, Lucy J. Colwell, Ned S. Wingreen

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


Specific protein-protein interactions are crucial in the cell, both to ensure the formation and stability of multiprotein complexes and to enable signal transduction in various pathways. Functional interactions between proteins result in coevolution between the interaction partners, causing their sequences to be correlated. Here we exploit these correlations to accurately identify, from sequence data alone, which proteins are specific interaction partners. Our general approach, which employs a pairwise maximum entropy model to infer couplings between residues, has been successfully used to predict the 3D structures of proteins from sequences. Thus inspired, we introduce an iterative algorithm to predict specific interaction partners from two protein families whose members are known to interact. We first assess the algorithm's performance on histidine kinases and response regulators from bacterial twocomponent signaling systems.We obtain a striking 0.93 true positive fraction on our complete dataset without any a priori knowledge of interaction partners, and we uncover the origin of this success. We then apply the algorithm to proteins from ATP-binding cassette (ABC) transporter complexes, and obtain accurate predictions in these systems as well. Finally, we present two metrics that accurately distinguish interacting protein families from noninteracting ones, using only sequence data.

Original languageEnglish (US)
Pages (from-to)12180-12185
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 25 2016

All Science Journal Classification (ASJC) codes

  • General


  • Coevolution
  • Direct coupling analysis
  • Maximum entropy
  • Paralogs
  • Protein-protein interactions


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