Modulation of in-membrane receptor clustering upon binding of multivalent ligands

In living cells and biomimetic systems alike, multivalent ligands in solution can induce clustering of membrane receptors. The link between the receptor clustering and the ligand binding remains, however, poorly defined. Using minimalist divalent ligands, we develop a model that allows quantifying the modulation of receptor clustering by binding of ligands with any number of binding sites. The ligands, with weak binding affinity for the receptor and with binding sites held together by flexible linkers, lead to nearly quantitative clustering upon binding in a wide range of experimental conditions, showing that efficient modulation of receptor clustering does not require pre-organization or large binding affinities per binding site. Simulations show that, in the presence of ligands with five or more binding sites, an on/off clustering response follows a very small change in receptor density in the membrane, which is consistent with the highly cooperative behavior of multivalent biomolecular systems.