  Functional proteins must fold with some minimal stability to a structure that
can perform a biochemical task. Here we use a simple model to investigate the
relationship between the stability requirement and the capacity of a protein to
evolve the function of binding to a ligand. Although our model contains no
built-in tradeoff between stability and function, proteins evolved function
more efficiently when the stability requirement was relaxed. Proteins with both
high stability and high function evolved more efficiently when the stability
requirement was gradually increased than when there was constant selection for
high stability. These results show that in our model, the evolution of function
is enhanced by allowing proteins to explore sequences corresponding to
marginally stable structures, and that it is easier to improve stability while
maintaining high function than to improve function while maintaining high
stability. Our model also demonstrates that even in the absence of a
fundamental biophysical tradeoff between stability and function, the speed with
which function can evolve is limited by the stability requirement imposed on
the protein.
