Shape changes in aroma-producing molecules determine the fragrances we detect

Shakespeare wrote 'a rose by any other name would smell as sweet.' But would it if the molecules that generate its fragrance were to change their shape? That's what Dr Kevin Ryan, Assistant Professor of Chemistry at The City College of New York (CCNY) and collaborators in the laboratory of Dr Stuart Firestein, Professor of Biology at Columbia University, set out to investigate. Their findings, reported today in the journal 'Chemistry and Biology,' shed new insight into how our sense of smell works and have potential applications in the design of flavours and fragrances.

When odour-producing molecules, known as odourants, pass through the nose, they trigger intracellular changes in a subset of the approximately 400 different varieties olfactory sensory neurones (OSN) housed in the nose's internal membrane tissue, Professor Ryan explained. The unique reaction pattern produced, known as the olfactory code, is sent as a signal to the brain, which leads to perception of odours.

Professor Ryan and his team wanted to learn how these receptor cells respond when odourants change their shape. They studied the odourant octanal, an eight-carbon aldehyde that occurs in many flowers and citrus fruits. Octanal is a structurally flexible molecule that can adapt to many different shapes by rotating its chemical bonds.

The researchers designed and synthesised eight-carbon aldehydes that resembled octanal, but had their carbon chains locked by adding one additional bond. These molecules were tested on genetically engineered OSNs known to respond to octanal. This work was done in Professor Firestein's laboratory at Columbia.

The aldehyde molecules that could stretch to their greatest length triggered strong activity in the OSNs. However, those molecules whose carbon chains were constrained into a U shape blocked the receptor and left the cell unable to sense octanal.

'Conformationally constrained odourants were more selective in the number of OSNs they activated,' Professor Ryan noted. 'The results indicate that these odourant molecules might be able to alter fragrance mixture odours in two ways: by muting the activity of flexible odourants present in a mixture and by activating a smaller subset of OSNs than chemically related flexible odourants. This would produce a different olfactory code signature.'

Olfactory receptors belong to the G-protein coupled receptor (GPCR) class of proteins, a family of molecules found in cell membranes throughout the body. Professor Ryan pointed out that half of all commercial pharmaceuticals work by interaction with proteins within this family. Thus, the findings could also have applications to GPCR drug design, as well.