  The interconnected processes of protein folding, mutations, epistasis, and
evolution have all been the subject of extensive analysis throughout the years
due to their significance for structural and evolutionary biology. The origin
(molecular basis) of epistasis (the non-additive interactions between
mutations) is still, nonetheless, unknown. The existence of a new perspective
on protein folding (a problem that needs to be conceived as an analytic whole)
will enable us to shed light on the origin of mutational epistasis at the
simplest level (within proteins) while also uncovering the reasons on why the
genetic background in which they occur (a key component of molecular evolution)
could foster changes in epistasis effects. Additionally, because mutations are
the source of epistasis, more research is needed to determine the impact of
posttranslational modifications (which have the potential to increase the
diversity of the proteome by several orders of magnitude) on both mutational
epistasis and protein evolvability. Finally, a protein evolution
thermodynamic-based analysis that does not consider specific mutational steps
or epistasis effects will be discussed. Our study explores the complex
processes behind the evolution of proteins upon mutations, clearing up some
previously unresolved issues and providing direction for further research in
this area.
