Implausibility of the vibrational theory of olfaction

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and ¹³C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d ₃₀ lacks the 1,380- to 1,550-cm ⁻¹ IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory. Significance The vibrational theory of olfaction posits detection of odorants through their vibrational frequencies rather than solely through “hand-in-glove” substrate/enzyme-like odorant–odorant receptor (OR) interactions. To test the theory, we compare responses of different human and mouse ORs toward deuterated and undeuterated isotopomers (isotopic atom isomers) of receptor-responsive odorants because isotopomers should differ in their molecular vibrational frequencies. However, no differences in receptor response are seen with any tested labeled/unlabeled odorant/receptor pairs. Because published behavioral studies have shown that humans can distinguish isotopomers, perireceptor events or impurities, rather than receptor-level vibrational effects, are suggest