Estimating the contribution of folding stability to non-specific epistasis in protein evolution

The extent of non-additive interaction among mutations or epistasis reflects the ruggedness of the fitness landscape, the mapping of genotype to reproductive fitness. In protein evolution, there is strong support for the importance and prevalence of epistasis, but whether there is a universal mechanism behind epistasis remains unknown. It is also unclear which of the biophysical properties of proteins—folding stability, activity, binding affinity, and dynamics—have the strongest contribution to epistasis. Here, we determine the contribution of selection for folding stability to epistasis in protein evolution. By combining theoretical estimates of the rates of molecular evolution and protein folding thermodynamics, we show that simple selection for folding stability implies that at least ~30% to ~60% of among amino acid substitutions would have experienced epistasis. Additionally, our model predicts substantial epistasis at marginal stabilities therefore linking epistasis to the strength of selection. Estimating the contribution of governing factors in molecular evolution such as protein folding stability to epistasis will provide a better understanding of epistasis that could improve methods in molecular evolution.