On the role of multiple states in allostery

Several physical mechanisms have been proposed to explain allostery. They differ by the number of internal states that they assume a protein to occupy, leaving open the question of what controls the emergence of one or several of these states. We study this question by introducing and analyzing a simplified model of protein allostery under a diversity of physical and evolutionary constraints. We find that two archetypal mechanisms can emerge through evolution, depending on the nature of these constraints: a single-state mechanism where ligand binding induces a displacement along a soft normal mode or a multi-state mechanism where ligand binding induces a switch across an energy barrier to a different stable state. Importantly, whenever the two mechanisms are possible, the second confers a stronger allosteric effect and thus a selective advantage. Our results provide an experimentally testable hypothesis for the functional importance of multiple states in proteins.