Role of fluctuations in ligand binding cooperativity of membrane receptors

Signal transduction upon binding of a ligand to a membrane protein can occur not only via allosteric conformational changes but also through fluctuations. We report a numerical study on the influence of conformational fluctuations on the cooperativity of a binding reaction in a simple model of an integral membrane receptor consisting of transmembrane helices. We find that small fluctuations lateral as well as perpendicular to the membrane can increase the cooperativity, with the former more dominant. Moreover, too much fluctuation induces negative cooperativity. Proteins with fewer than four helices do not show positive cooperativity under any circumstances. This behavior is rather robust, and independent of the receptor topology or ligand size. Fluctuations measured in all-atom molecular dynamics simulations of a G-protein coupled receptor fall within the predicted region of maximum cooperativity.