Evidence from computational infrared spectroscopy against vibrational detection of propionate by human olfactory...

Despite its ubiquity in nature, some details of the animal olfactory system remain unclear. One such mystery is the mechanism by which olfactory receptors (ORs) recognize the olfactant molecules they bind to. Some evidence indicates that ORs can distinguish between molecules that differ only in isotopic composition, suggesting that olfactants' vibrational modes may play a role in their recognition. In 2023, the first experimental structure of a human olfactory receptor-OR51E2-was produced, providing opportunity to shed additional light on this problem computationally. We simulate the infrared spectrum of the olfactant propionate ([Formula: see text]), as well as all its possible deuterations, in the OR51E2 binding site by quantum mechanics/molecular mechanics, with atomic positions taken at 25 time points over a 500 ns molecular dynamics simulation. The protein environment does not change the vibrational spectrum qualitatively, even at physiological temperature. The high-frequency C-H modes are about [Formula: see text] higher in energy than their deuterated counterparts, while the modes associated with the carboxyl group are almost unaffected by the C/H isotopic substitution. Because [Formula: see text] binds to OR51E2 primarily via the carboxyl end, this result means that a vibrational component to propionate detection is unlikely.