Allostery for free? Scenarios for the evolutionary origin of allostery in proteins.

Protein allostery underpins many molecular processes in the cell and long standing efforts have sought to understand the physical mechanisms of allostery. The evolutionary origin of allostery on the other hand remains difficult to explain. For instance, latent allostery, or allosteric behavior not part of the protein's native function, is commonly observed yet can not be explained by direct selection alone. What is the origin of this latent allostery? Here use simplified physical models of proteins to show that allostery can emerge, not from direct selection, but indirectly, from selection on functions of the active site, such as binding specificity. We find that such selections lead to a spatially extended region of mutationally sensitivity where mutations act allosterically to modulate the function of the active site from a distance. Models with such architecture are "primed" with latent allostery and can act as evolutionary starting points for allosteric regulation.