Direct coupling analysis of epistasis in allosteric materials

In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug design, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in pa...

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Veröffentlicht in:PLoS computational biology Jg. 16; H. 3; S. e1007630
Hauptverfasser: Bravi, Barbara, Ravasio, Riccardo, Brito, Carolina, Wyart, Matthieu
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 01.03.2020
Public Library of Science (PLoS)
Schlagworte:
Allosteric properties
Analysis
Biology and Life Sciences
Cost analysis
Couplings
Drug development
Empirical analysis
Epistasis
Evolution
Gene mutation
Generic drugs
Ligands
Medicine and Health Sciences
Mutation
Nucleotide sequence
Physics
Protein binding
Proteins
Research and Analysis Methods
Software
Iran
Switzerland
ISSN:1553-7358, 1553-734X, 1553-7358
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Zusammenfassung:In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug design, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in particular on the existence of long-range evolutionary couplings between distant amino-acids mediating allostery. Here we propose a resolution of this conundrum, by studying epistasis and its inference in models where an allosteric material is evolved in silico to perform a mechanical task. We find in our model the four types of epistasis (Synergistic, Sign, Antagonistic, Saturation), which can be both short or long-range and have a simple mechanical interpretation. We perform a Direct Coupling Analysis (DCA) and find that DCA predicts well the cost of point mutations but is a rather poor generative model. Strikingly, it can predict short-range epistasis but fails to capture long-range epistasis, in consistence with empirical findings. We propose that such failure is generic when function requires subparts to work in concert. We illustrate this idea with a simple model, which suggests that other methods may be better suited to capture long-range effects.
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The authors have declared that no competing interests exist.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1007630