The influence of cell surface receptor clustering on the thermodynamics of ligand binding and the kinetics of its dissociation.

We show that an equilibrium model for the clustering, by divalent ligand, of homogeneous plasma membrane-bound divalent receptors that do not change conformation predicts Scatchard plots with positive second derivatives (concave up). The result is thermodynamically indistinguishable from predictions based upon receptors that are heterogeneous for ligand, or that change conformation in a negatively cooperative way when ligand binds. A more general formulation of the theory, which allows application to dissociation kinetics, predicts that the dissociation of labeled ligand is accelerated in the presence of excess cold ligand and, moreover, that the accelerated dissociation has at least two components. The theory is briefly illustrated by fitting five different sets of data, at several temperatures for two different systems, with parameter values that are well within physically meaningful ranges. The model presented is the simplest and least ad hoc explanation thus far proposed as the basis for the kinetic phenomena, and raises the possibility that the numerous experiments in which such data are observed are primarily minifestations of cell surface clustering.