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Using the Mutation-Selection Framework to Characterize Selection on Protein Sequences
Open AccessArticle

Selection for Protein Stability Enriches for Epistatic Interactions

1
Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
2
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Genes 2018, 9(9), 423; https://doi.org/10.3390/genes9090423
Received: 4 June 2018 / Revised: 30 July 2018 / Accepted: 14 August 2018 / Published: 21 August 2018
(This article belongs to the Special Issue Evolution and Structure of Proteins and Proteomes)
A now classical argument for the marginal thermodynamic stability of proteins explains the distribution of observed protein stabilities as a consequence of an entropic pull in protein sequence space. In particular, most sequences that are sufficiently stable to fold will have stabilities near the folding threshold. Here, we extend this argument to consider its predictions for epistatic interactions for the effects of mutations on the free energy of folding. Although there is abundant evidence to indicate that the effects of mutations on the free energy of folding are nearly additive and conserved over evolutionary time, we show that these observations are compatible with the hypothesis that a non-additive contribution to the folding free energy is essential for observed proteins to maintain their native structure. In particular, through both simulations and analytical results, we show that even very small departures from additivity are sufficient to drive this effect. View Full-Text
Keywords: thermodynamic stability; epistasis; molecular evolution; purifying selection thermodynamic stability; epistasis; molecular evolution; purifying selection
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Posfai, A.; Zhou, J.; Plotkin, J.B.; Kinney, J.B.; McCandlish, D.M. Selection for Protein Stability Enriches for Epistatic Interactions. Genes 2018, 9, 423.

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