Abstract
In allosteric proteins, binding a ligand can affect function at a distant location, for example, by changing the binding affinity of a substrate at the active site. The induced fit and population shift models, which differ by the assumed number of stable configurations, explain such cooperative binding from a thermodynamic viewpoint. Yet, understanding what mechanical principles constrain these models remains a challenge. Here, we provide an empirical study on 34 proteins supporting the idea that allosteric conformational change generally occurs along a soft elastic mode presenting extended regions of high shear. We argue, based on a detailed analysis of how the energy profile along such a mode depends on binding, that in the induced fit scenario, there is an optimal stiffness k(a)(∗) ∼ 1/N for cooperative binding, where N is the number of residues. We find that the population shift scenario is more robust to mutations affecting stiffness because binding becomes more and more cooperative with stiffness up to the same characteristic value k(a)(∗), beyond which cooperativity saturates instead of decaying. We numerically confirm these findings in a nonlinear mechanical model. Dynamical considerations suggest that a stiffness of order k(a)(∗) is favorable in that scenario as well, supporting that for proper function, proteins must evolve a functional elastic mode that is softer as their size increases. In consistency with this view, we find a fair anticorrelation between the stiffness of the allosteric response and protein size in our data set.