Olfactory Perception Regularities of Structurally Related γ-Lactones: Insights from OR2W1 Selectivity

Abstract Olfactory receptor recognition of odorants is generally considered to involve dynamic receptor–ligand interactions rather than a rigid lock-and-key mechanism. To investigate how structurally related odorants are differentially recognized, a homologous series of γ-lactones differing only in alkyl side-chain length was systematically evaluated using the human olfactory receptor OR2W1. Cellular assays demonstrated that OR2W1 activation initially increased and subsequently decreased with increasing side-chain length, with γ-nonalactone producing the strongest concentration-dependent response (EC50 = 40.27 ± 2.33 μM). Molecular modeling suggested that γ-nonalactone adopted the most favorable binding mode and exhibited the lowest predicted binding free energy toward OR2W1. Site-directed mutagenesis of representative binding-site residues further supported the functional evidence of the predicted receptor–ligand interactions. Collectively, these results suggest that the structural adaptability of the OR2W1 binding pocket contributes to the differential recognition of structurally related γ-lactones within a limited physicochemical space. This study provides molecular-level evidence for the structure–activity relationship governing γ-lactone recognition by OR2W1 and offers mechanistic insights into odorant recognition by broadly tuned human olfactory receptors.