Protein folding and binding can emerge as evolutionary spandrels through structural coupling

Binding interactions between proteins and other molecules mediate numerous cellu-lar processes, including metabolism, signaling, and regulation of gene expression. These interactions evolve in response to changes in the protein’s chemical or physical envi-ronment (such as the addition of an antibiotic), or when genes duplicate and diverge. Several recent studies have shown the importance of folding stability in constraining protein evolution. Here we investigate how structural coupling between protein folding and binding – the fact that most proteins can only bind their targets when folded – gives rise to evolutionary coupling between the traits of folding stability and binding strength. Using biophysical and evolutionary modeling, we show how these protein traits can emerge as evolutionary “spandrels ” even if they do not confer an intrinsic fitness advantage. In particular, proteins can evolve strong binding interactions that have no functional role but merely serve to stabilize the protein if misfolding is dele-terious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutation events. These observations may ex