Computed isotope shifts of high-frequency vibrational modes exceed thermal noise in propionate bound to a human olfactory receptor

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 computational scientists an opportunity to shed additional light on this problem. We compute the infrared spectrum of the olfactant propionate (C2H5COO–) 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. By comparing the spectra for all 32 possible hydrogen/deuterium isotopic combinations in propionate and across the time snapshots, we estimate the relative strength of the isotope effects and thermal fluctuations in the vibrational energy of C2H5COO–. The high-frequency C–H modes are are about 800 cm^{-1} higher in energy than their deuterated counterparts, a large separation relative both to their fluctuations over time and to the thermal energy available at physiological temperature. Lower-frequency vibrations do not display such a clear isotopic separation. Thus, any vibrational component to olfactant recognition—especially one that allows distinguishing between isotopes—is likely to involve these high-frequency modes.