Abstract
Do the amino acid sequence identities of residues that make contact across protein interfaces covary during evolution? If so, such covariance could be used to predict contacts across interfaces and assemble models of biological complexes. We find that residue pairs identified using a pseudo-likelihood-based method to covary across protein-protein interfaces in the 50S ribosomal unit and 28 additional bacterial protein complexes with known structure are almost always in contact in the complex, provided that the number of aligned sequences is greater than the average length of the two proteins. We use this method to make subunit contact predictions for an additional 36 protein complexes with unknown structures, and present models based on these predictions for the tripartite ATP-independent periplasmic (TRAP) transporter, the tripartite efflux system, the pyruvate formate lyase-activating enzyme complex, and the methionine ABC transporter.DOI: http://dx.doi.org/10.7554/eLife.02030.001.
Highlights
IntroductionRecent work has demonstrated the accuracy of coevolution-based contact prediction for monomeric proteins using a global statistical model (Thomas et al, 2008) to distinguish between direct and indirect couplings (Marks et al, 2011; Morcos et al, 2011; Hopf et al, 2012; Nugent and Jones, 2012; Jones et al, 2012; Lapedes et al, 2012; Marks et al, 2012; Sułkowska et al, 2012; Kamisetty et al, 2013)
Amino acid residue coevolution has been used to predict residue–residue interactions across interfaces with local statistical models (Pazos et al, 1997; Halperin et al, 2006). The accuracy of these models is reduced by the confounding of direct and indirect correlations (Lapedes et al, 1999; Weigt et al, 2009); the application of global statistical models to coevolution-based contact prediction across interfaces has been limited to the case of the histidine-kinase/response-regulator two component system (Burger and van Nimwegen, 2008; Weigt et al, 2009; Schug et al, 2009; Dago et al, 2012)
Our results demonstrate unequivocally that there is strong selective pressure at protein–protein interfaces beyond simple residue conservation, and that co-evolving residue pairs are nearly always in contact in the protein complex
Summary
Recent work has demonstrated the accuracy of coevolution-based contact prediction for monomeric proteins using a global statistical model (Thomas et al, 2008) to distinguish between direct and indirect couplings (Marks et al, 2011; Morcos et al, 2011; Hopf et al, 2012; Nugent and Jones, 2012; Jones et al, 2012; Lapedes et al, 2012; Marks et al, 2012; Sułkowska et al, 2012; Kamisetty et al, 2013). While early approaches relied on estimating an inverse covariance matrix (Marks et al, 2011; Morcos et al, 2011; Jones et al, 2012), more recent studies have shown that a pseudolikelihood-based approach (Balakrishnan et al, 2011) results in more accurate predictions (Ekeberg et al, 2013; Kamisetty et al, 2013) for a range of alignment sizes and protein lengths In contrast to this rich body of work for monomeric proteins, relatively little is known about the utility of such statistical models in predicting protein–protein interactions. The accuracy of these models is reduced by the confounding of direct and indirect correlations (Lapedes et al, 1999; Weigt et al, 2009); the application of global statistical models to coevolution-based contact prediction across interfaces has been limited to the case of the histidine-kinase/response-regulator two component system (Burger and van Nimwegen, 2008; Weigt et al, 2009; Schug et al, 2009; Dago et al, 2012)
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