Coevolution-based inference of amino acid interactions underlying protein function

Abstract
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Abstract

Protein function arises from a poorly understood pattern of energetic interactions between amino acid residues. Sequence-based strategies for deducing this pattern have been proposed, but lack of benchmark data has limited experimental verification. Here, we extend deep-mutation technologies to enable measurement of many thousands of pairwise amino acid couplings in several homologs of a protein family - a deep coupling scan (DCS). The data show that cooperative interactions between residues are loaded in a sparse, evolutionarily conserved, spatially contiguous network of amino acids. The pattern of amino acid coupling is quantitatively captured in the coevolution of amino acid positions, especially as indicated by the statistical coupling analysis (SCA), providing experimental confirmation of the key tenets of this method. This work exposes the collective nature of physical constraints on protein function and clarifies its link with sequence analysis, enabling a general practical approach for understanding the structural basis for protein function.

Data availability

Mutation data have been deposited in the Dryad database under accession code doi:10.5061/dryad.gk4m1

The following data sets were generated

1. Salinas VH
2. Ranganathan R
(2017) Data from: The role of feeding morphology and competition in governing the diet breadth of sympatric stomatopod crustaceans
| Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

http://dx.doi.org/10.5061/dryad.gk4m1

Article and author information

Author details

Rama Ranganathan

Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
ranganathanr@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5463-8956
Victor H Salinas

Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.

Funding

National Institutes of Health (RO1GM123456)

Victor H Salinas

Welch Foundation (I-1366)

Rama Ranganathan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.