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 
(13)C 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-d30 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.