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

TL;DR

This paper explores how structural coupling between protein folding and binding can lead to the emergence of traits as evolutionary spandrels, influencing protein evolution and interactions without direct functional advantages.

Contribution

It introduces biophysical and evolutionary models showing how folding and binding traits can evolve as spandrels, explaining nonfunctional interactions and evolutionary constraints.

Findings

Proteins can evolve strong binding without functional roles.

Nonfunctional interactions are common in high-throughput assays.

Evolutionary paths are constrained by biophysical trade-offs.

Abstract

Binding interactions between proteins and other molecules mediate numerous cellular processes, including metabolism, signaling, and regulation of gene expression. These interactions evolve in response to changes in the protein's chemical or physical environment (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 deleterious. Furthermore, such proteins may have divergent fates, evolving to bind or not bind their targets depending on random mutation events. These observations may explain the abundance of apparently nonfunctional interactions among proteins observed in high-throughput assays. In contrast, for proteins with both functional binding and deleterious misfolding, evolution may be highly predictable at the level of biophysical traits: adaptive paths are tightly constrained to first gain extra folding stability and then partially lose it as the new binding function is developed. These findings have important consequences for our understanding of fundamental evolutionary principles of both natural and engineered proteins.