Ligand-induced receptor multimerization achieves specificity enhancement of kinetic proofreading without associated costs

Kinetic proofreading (KPR) is a commonly invoked mechanism for specificity enhancement of receptor signaling. However, specificity enhancement comes at a cost of nonequilibrium energy input and signal attenuation. We show that ligand-induced multimeric receptor assembly can enhance receptor specificity to the same degree as KPR, yet without the need for out-of-equilibrium energy expenditure and signal loss. We show how multimeric receptor specificity enhancement arises from the amplification of affinity differences via sequential progression down a free energy landscape. We also show that multimeric receptor ligand recognition is more robust to stochastic fluctuations and molecular noise than KPR receptors. Finally, we show that multimeric receptors perform signaling tasks beyond specificity enhancement like absolute discrimination and aspects of ligand antagonism. Our results suggest that multimeric receptors may serve as a potent mechanism of ligand discrimination comparable to and potentially with more advantages than traditional proofreading.