Receptor-Selective and Concentration-Dependent Responses to Vanillin–Ethyl Vanillin Mixtures: An Integrated Sensory and Statistical-Physics Analysis

Abstract Vanillin (V) and ethyl vanillin (EV) are frequently combined in flavor formulations, but composition-dependent sensory profiles and olfactory receptor responses remain unclear. Sensory evaluation showed stronger creamy notes in EV-rich mixtures and stronger vanilla and sweet notes in V-rich mixtures compared with the 1:1 mixture. Among four human olfactory receptors tested in HEK293 cells, OR2J2 and OR10G4 responded most strongly. OR2J2 showed no consistent supra-additivity. OR10G4 exhibited supra-additivity with one component fixed at 100.00–500.00 μmol/L and the other varied within direction-dependent low-to-intermediate ranges of 1.95–500.00 μmol/L, shifting to subadditivity when the fixed component reached 1000.00 μmol/L. Statistical-physics monolayer modeling suggested that receptor selectivity reflected stronger energetic stabilization of V by OR2J2 and greater configurational adaptability of EV within OR10G4. Single-ligand, simultaneous dual-ligand, and sequential docking revealed vertically separated co-occupancy in OR2J2 but side-by-side, order-dependent accommodation in OR10G4. These findings advance understanding of odorant mixture perception and inform future formulation studies.