Can your nose tell left from right?

Many of the molecules important to life are chiral: they have left- and right-handed forms. Thus Dorothy Sayers’s The Documents in the Case centres on the distinction between the synthetic poison, muscarin, with its equal mix of left and right forms, and the single enantiomer ((L-+-muscarine) found in funghi. The distinction can be critical, as for cocaine, thalidomide , or thyroxine. Industries now synthesise drug molecules of chosen handedness.

Our sense of smell lets us to detect and often identify many hundreds of molecules. Many olfactants are also chiral. A major database (Leffingwell) lists over 400 such enantiomer pairs and their reported odours. Do left and right handed molecules really smell different or not? The quick answer would be that about 60% of the pairs smell alike and 40% smell different. Such numbers are complicated by subjectivity and by what one believes of subtle differences. Certainly the odours appear identical in some cases (like ‘amber, woody, cedar wood’ versus ‘woody, amber, spicy’). Again, in other cases (‘blackcurrant leaf, tropical note of passion fruit’ versus ‘rubber, mercaptan note, sulphuraceous’) they smell very different indeed. This is puzzling. How might the nose distinguish them?
                
Structure of (4R)-(-)-carvone (axial)  Structure of (4R)-(-)-carvone (equatorial)

The simplest idea might be that the odorant molecule’s shape must match that of some receptor. Putting a left-handed molecule into a right-hand receptor would be like trying to put your left hand into your right-hand glove: not a comfortable fit. So, if shape alone matters, virtually all pairs should smell different, contrary to observation.

Actuation controlled by shape, a “lock and key” description, is the basis for much drug design activity. But it is far less successful for scents. Odorants very similar in shape can smell utterly different (e.g., ferrocene and nickelocene), but ones utterly different in shape can smell the same (e.g., hydrogen sulphide and decaborane).

Other theories are based on properties such as vibration frequencies, with only a modest dependence on shape (“swipe card” models), and would suggest enantiomers should smell much the same. Again, experiment disagrees. Neither of these models gives a full explanation, at least in their simplest forms.

Our analysis of hundreds of molecules having left- and right-handed versions identifies a simple and general rule: enantiomers smell different only when the molecules have a special type of flexibility. This looks counter-intuitive for current theories, at least in their simplest forms. Flexible scent molecules should be able to wriggle to activate the same receptors, contrary to simple shape ideas. But if some shape-independent property of nasal receptors is crucial, then what is the role of flexibility? So what is going on?

Flexible molecules can explore a wider range of configurations, and somehow this flexibility allows left and right handed molecules to be distinguished. Their average geometries will differ in a given receptor, and perhaps this shape difference changes some molecular property the receptor recognises (such as vibrational frequency). Or perhaps some transient conformation is critical and is only achieved by one of the molecules. Think back to the hand in glove analogy. If your hands are held flat and rigid, the left- and right-hands could each fit into a left hand glove, and could still make a few moves (like moving fingers apart) that might activate a process. But they’d do so roughly equally effectively. Now if actuation needed you to curl up your fingers, then only a flexible left hand can manage. Real olfactory receptors operate in ways that are still being discussed. But this analogy emphasises the important point that whatever initiates a signal to your brain may depend on more than the average equilibrium shape of the molecule.

This is based on our paper

Jennifer C Brookes, Andrew Horsfield and A M Stoneham 2008, "Odour Character Differences for Enantiomers Correlate with Molecular Flexibility" Journal of the Royal Society: Interface 5 10.1098/rsif.2008.0165

All authors belong to the LCN; Jenny Brookes and Marshall Stoneham from UCL, Andrew Horsfield from Imperial College.

 

 

Cyclohexane at 600K & 20ps

(4R)-(-)-carvone at 600K & 20ps

(4S)-(+)-fenchone at 600K & 20ps

 

       
The images shown above are of the three compounds used in simulations to examine the conformational space occupied by these compounds, which influences how they are perceived in olfactory systems.

Notes for Editors:

About the London Centre for Nanotechnology

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