Epistasis and intramolecular networks in protein evolution

Proteins are molecular machines composed of complex, highly connected amino acid networks. Their functional optimization requires the reorganization of these intramolecular networks by evolution. In this review, we discuss the mechanisms by which epistasis, that is, the dependence of the effect of a mutation on the genetic background, rewires intramolecular interactions to alter protein function. Deciphering the biophysical basis of epistasis is crucial to our understanding of evolutionary dynamics and the elucidation of sequence-structure-function relationships. We featured recent studies that provide insights into the molecular mechanisms giving rise to epistasis, particularly at the structural level. These studies illustrate the convoluted and fascinating nature of the intramolecular networks co-opted by epistasis during the evolution of protein function.