Deciphering the dynamic binding of spicy odorants to human olfactory receptors

In this study, we compiled three categories of odorants with spicy aromas: anise class, clove class, and cinnamon class. We aimed to use molecular dynamics simulation techniques to uncover potential regularities in the activation mechanisms of the same odorant across different olfactory receptors, or vice versa, the activation mechanisms of different odorants on the same olfactory receptor. Here, molecular dynamics simulation results reveal that anisaldehyde and estragole preferentially bind to TYR residues, thereby activating the corresponding olfactory receptors. Both eugenol and isoeugenol activate OR5D18 at similar binding sites, but ultimately lead to differential conformational changes in the olfactory receptor. Additionally, the binding conformations of eugenol and methyl eugenol are nearly identical, whereas cinnamaldehyde and cinnamyl alcohol, methyl cinnamaldehyde, exhibit distinct binding conformations with the olfactory receptor. These results underscore how subtle structural changes can impact the binding mechanism of odorants.