  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.
