Competitive binding predicts nonlinear responses of olfactory receptors to complex mixtures

Abstract

Significance Predicting the response of the olfactory system to natural odors, typically complex mixtures of many molecules, is a major challenge. Here, we show that the nonlinear mixing response of many mammalian olfactory receptors is largely explained by the competition of molecules for binding sites. The resulting model of receptor responses provides a significant step toward synthesizing odors by adding “odor primaries” just as arbitrary colors can be created from mixtures of three primary colors. In color vision, the quantitative rules for mixing lights to make a target color are well understood. By contrast, the rules for mixing odorants to make a target odor remain elusive. A solution to this problem in vision relied on characterizing receptor responses to different wavelengths of light and subsequently relating these responses to perception. In olfaction, experimentally measuring receptor responses to a representative set of complex mixtures is intractable due to the vast number of possibilities. To meet this challenge, we develop a biophysical model that predicts mammalian receptor responses to complex mixtures using responses to single odorants. The dominant nonlinearity in our model is competitive binding (CB): Only one odorant molecule can attach to a receptor binding site at a time. This simple framework predicts receptor responses to mixtures of up to 12 monomolecular odorants to within 15% of experimental observations and provides a powerful method for leveraging limited experimental data. Simple extensions of our model describe phenomena such as synergy, overshadowing, and inhibition. We demonstrate that the presence of such interactions can be identified via systematic deviations from the competitive-binding model.