CovET: A Covariation-Evolutionary Trace Method That Identifies Protein Structure-Function Modules

Authors

Daniel M Konecki
Spencer Hamrick
Chen Wang
Melina A Agosto
Theodore G Wensel
Olivier Lichtarge

Publication Date

7-1-2023

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2023.104896

PMID

37290531

PMCID

PMC10338321

PubMedCentral® Posted Date

6-7-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Binding Sites, Evolution, Molecular, Phylogeny, Receptors, G-Protein-Coupled, Sequence Alignmentk, protein motifs, allosteric determinants, coevolution, epistasis, functional sites

Abstract

Measuring the relative effect that any two sequence positions have on each other may improve protein design or help better interpret coding variants. Current approaches use statistics and machine learning but rarely consider phylogenetic divergences which, as shown by Evolutionary Trace studies, provide insight into the functional impact of sequence perturbations. Here, we reframe covariation analyses in the Evolutionary Trace framework to measure the relative tolerance to perturbation of each residue pair during evolution. This approach (CovET) systematically accounts for phylogenetic divergences: at each divergence event, we penalize covariation patterns that belie evolutionary coupling. We find that while CovET approximates the performance of existing methods to predict individual structural contacts, it performs significantly better at finding structural clusters of coupled residues and ligand binding sites. For example, CovET found more functionally critical residues when we examined the RNA recognition motif and WW domains. It correlates better with large-scale epistasis screen data. In the dopamine D2 receptor, top CovET residue pairs recovered accurately the allosteric activation pathway characterized for Class A G protein-coupled receptors. These data suggest that CovET ranks highest the sequence position pairs that play critical functional roles through epistatic and allosteric interactions in evolutionarily relevant structure-function motifs. CovET complements current methods and may shed light on fundamental molecular mechanisms of protein structure and function.

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