Selection for Protein Stability Enriches for Epistatic Interactions
By Anna Posfai, Juannan Zhou, Joshua B. Plotkin, Justin B. Kinney, David M. McCandlish. 2018
9 citations recorded by the source corpus.
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.
Subfields: Genetics, Materials Chemistry, Molecular Biology
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Citations in the corpus
- Revealing evolutionary constraints on proteins through sequence analysis (2018, background): “This phenomenon is known as global [10,14] or nonspecific [9] epistasis, and its relevance has been shown in evolution experiments [14], over and above contributions from specific epistasis [9, 15].”