A unified framework and an alternative mechanism for allosteric regulation

Allosteric regulation is an important property for many proteins. Several models have been proposed to explain the allosteric effect, such as the concerted MWC (Monod, Wyman, Changeux) model, the sequential KNF (Koshland, Nemethy, Filmer) model, and recent population shift models. Here we discuss a unified theoretical framework to describe allosteric effects. The existing models appear as special cases of the framework. The theoretical work also reveals an alternative mechanism currently overlooked. Theoretically it is possible that the reactivity of a protein is limited by some internal conformational change step (due to slow effective diffusion along rugged potential surfaces). Effector binding may modify the ruggedness and thus the protein dynamics and reactivity. Compared to conventional models, the new mechanism has less requirements on the mechanical properties of an allosteric protein to propagate mechanical signals over long distances. Thus some signal transduction proteins may adopt the new mechanism or a combination with conventional mechanisms. For a positive allosteric enzyme functioning under the new mechanism, the theory predicts that compared to the case with effector binding, an enzyme without effector has: 1) larger temperature dependence; 2) larger effect of dynamic disorders; 3) smaller collective and individual dynamic fluctuations; 4) no requirement for a well-defined mechanical strain relaying network; 5) no requirement for large conformational change upon effector binding. Opposite predictions of (1)-(3) are for negative allosteric proteins