Most receptors do not interact with the entirety of their ligand molecules. Rather, there are usually parts of the ligand molecule that can be modified with minimal impact on receptor binding and activation, while other parts of the ligand molecule are more critical. Indeed, one can think of receptors as detectors of these critical molecular features. For olfactory receptors, these hypothesized features have been called "odotopes" in recognition of their similarity to "epitopes" in immunology (Mori and Shepherd, 1994).

We have designed a large number of experiments using sets of odorant molecules differing systematically in chemical structure in order to explore the detection of molecular features by odorant receptors. In our first experiment dealing with this issue, we found that each of two ethyl esters stimulated 2DG uptake in a part of the bulb that was not activated by either of two isoamyl esters (Johnson et al., 1998). Conversely, each of the two isoamyl esters activated a distinct location that was not stimulated by either of the ethyl esters. The activity patterns were consistent with the recognition of the ethyl and isoamyl groups as distinct molecular features. In addition, all four esters stimulated a larger, overlapping area of the bulb, consistent with the overall similarity in their core structure.  

We then tested a set of five odorants sharing a straight-chained, saturated hydrocarbon structure but differing in the nature of their oxygen-containing functional groups to determine whether the olfactory system would recognize functional groups as distinct molecular features (Johnson and Leon, 2000a).  While all of these odorants overlapped in their stimulation of a cluster of glomeruli in more posterior bulb regions, consistent with their shared straight-chain core structure, they activated distinct clusters of glomeruli in more anterior regions, consistent with the notion that the functional groups are recognized as distinct features in a combinatorial code. 

When we used another set of odorants that shared a carboxylic acid functional group but that differed greatly in their hydrocarbon structures, the anterior clusters of activated glomeruli overlapped, consistent with their shared functional group, whereas the more posterior activity patterns differed greatly, consistent with the recognition of the different hydrocarbon structures as distinct molecular features in a combinatorial code (Johnson and Leon, 2000b). The conclusions from these two experiments were consistent with the recognition of functional group-related features by the more anterior glomeruli and hydrocarbon structural features by the more posterior glomeruli. The different combinations of molecular features in different odorants could thereby combine to generate distinct activity patterns and unique odor perceptions. 

In our subsequent research, we found that certain hydrocarbon elements such as benzene rings (Farahbod et al., 2006), methyl-substituted bicyclic structures (Johnson et al., 2006a), and triple bonds (Johnson et al., 2006b) also can be recognized as distinct molecular features. However, if there are multiple "features" in the same molecule, interactions can occur, leading to patterns of activity that are not entirely predictable from the individual functional groups or hydrocarbon structural elements.