Selection for Protein Stability Enriches for Epistatic Interactions
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 21, 2018
- Source ID
- 10.3390/genes9090423
Entities
People
- Anna Posfai
- David Mccandlish
- Joshua B. Plotkin
- Juannan Zhou
- Justin Kinney
Organizations
- Army Research Office
- David and Lucile Packard Foundation