Mutual modulation between membrane-embedded receptor clustering and ligand binding in lipid membranes

Thanks largely to a cooperative chelate effect, clustered membrane-embedded proteins favourably bind to multivalent ligands in solution and, conversely, a multivalent receptor can induce the clustering of membrane-embedded proteins. Here, we use a chemical model to show that the binding of a monovalent ligand and the clustering of a membrane-embedded receptor are closely related processes that modulate each other without the contribution of any apparent multivalence effect. Clearly, the confinement of the receptor within the surface reveals cooperative effects between clustering and binding that are too weak to detect in bulk-solution systems. This work shows that for membrane-embedded receptors that undergo some degree of spontaneous clustering, analyses based on multivalence-mediated cooperativity are insufficient to describe fully the molecular recognition events induced by ligands in solution. Instead, a binding-clustering thermodynamic cycle is proposed for the analysis of the interaction of any kind of ligand with membrane-embedded receptors.