Shape theory of olfaction

The Shape theory of smell proposes that a molecule's smell character is due to its molecular shape, molecular size and functional groups.^[1] It has also been described by a 'lock and key' mechanism by which a scent molecule fits into olfactory receptors in the nasal epithelium.

History

In 1949, R.W. Moncrieff published an article in American Perfumer called "What is odor: a new theory," which used Linus Pauling's notion of shape-based molecular interactions to propose a shape-based theory of odor.^[2] This superseded the older vibration theory of olfaction and remains the mainstream theory, in both commercial fragrance chemistry and academic molecular biology. Three years after Moncrieff proposed the theory, John Amoore speculated further that the over ten thousand smells distinguishable by the human olfaction system resulted from the combination of seven basic primary odors correlating to odor receptors for each, much as the spectrum of perceived colors in visible light is generated by the activation of three primary color receptors. Amoore's seven primary odors included sweaty, spermous, fishy, malty, urinous and musky. His most convincing work was done on the camphoraceous odor, for which he posited a hemispherical socket in which spherical molecules, such as camphor, cyclooctane, and naphthalene could bind.

When Linda Buck and Richard Axel published their Nobel Prize winning research on the olfactory receptors in 1991, they identified in mice 1,000 G-protein-coupled receptors used for olfaction.^[3] Since all types of G-protein receptors currently known are activated through binding of molecules with highly specific conformations, or shape, it is assumed that olfactory receptors operate in a similar fashion. Further research on human olfaction systems identified 347 olfactory receptors.

The most recent shape theory, also known as odotope theory or Weak Shape Theory, holds that a combination of activated receptors is responsible for any one smell, as opposed to the older model of one receptor, one shape, one smell. Receptors in the odotope model recognize only small structural features on each molecule, and the brain is responsible for processing the combined signal into an interpreted smell. Much current work on shape theory focuses on neural processing, rather than the specific interaction between odorant and receptor that generates the original signal.^[4]

Support

Numerous studies have been conducted to elucidate the complex relationship between the shape of an odorous molecule and its perceived smell character, and fragrance chemists have proposed structure models for the smells of amber, sandalwood, and camphor, among others.

A study by Leslie B. Vosshall and Andreas Keller, published in Nature Neuroscience in 2004, tested several key predictions of the competing vibration theory and found no experimental support for it.^[5][6] The data were described by Vosshall as "consistent with the shape theory," although she added that "they don't prove the shape theory."^[7]

Another study also showed that molecular volume of odorants can determine the upper limits of neural responses of olfactory receptors in Drosophila.^[8]

A 2015 Chemical & Engineering News article on the "shape" versus "vibration" debate notes that in the "acrimonious, nearly two-decade-long controversy...on the one side are a majority of sensory scientists who argue that our odorant receptors detect specific scent molecules on the basis of their shapes and chemical properties. On the other side are a handful of scientists who posit that an odorant receptor detects an odor molecule's vibrational frequencies."^[9] The article indicates that a new study, led by Block et al., takes aim at the vibrational theory of olfaction, finding no evidence that olfactory receptors distinguish vibrational states of molecules. Specifically, Block et al.^[10] report that the human musk-recognizing receptor, OR5AN1, identified using a heterologous olfactory receptor expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse olfactory receptors, responded similarly to normal, deuterated, and carbon-13 isotopomers of their respective ligands, paralleling results found with the musk receptor OR5AN1. Based on these findings, the authors conclude that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other olfactory receptors examined. Additionally, theoretical analysis by the authors shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. The authors conclude: “These and other concerns about electron transfer at olfactory receptors, together with our extensive experimental data, argue against the plausibility of the vibration theory.”

In commenting on this work, Vosshall writes “In PNAS, Block et al…. shift the “shape vs. vibration” debate from olfactory psychophysics to the biophysics of the ORs themselves. The authors mount a sophisticated multidisciplinary attack on the central tenets of the vibration theory using synthetic organic chemistry, heterologous expression of olfactory receptors, and theoretical considerations to find no evidence to support the vibration theory of smell."^[1] While Turin comments that Block used "cells in a dish rather than within whole organisms" and that "expressing an olfactory receptor in human embryonic kidney cells doesn't adequately reconstitute the complex nature of olfaction..." Vosshall responds "Embryonic kidney cells are not identical to the cells in the nose .. but if you are looking at receptors, it's the best system in the world."^[9]

Challenges

• Despite numerous studies, shape theory has yet to discover shape-odor relations with great predictive power.^[11]
• Similarly shaped molecules with different molecular vibrations have different smells (metallocene experiment and deuterium replacement of molecular hydrogen).^[12] However this challenge is contrary to the results obtained with silicon analogues of bourgeonal and lilial, which despite their differences in molecular vibrations have similar smells and similarly activate the most responsive human receptor, hOR17-4,^[13] and with studies showing that the human musk receptor OR5AN1 responds identically to deuterated and non-deuterated musks.^[10]
• Differently shaped molecules with similar molecular vibrations have similar smells (replacement of carbon double bonds by sulfur atoms and the disparate shaped amber odorants).
• Hiding functional groups does not hide the group's characteristic odor. However this is not always the case, since ortho-substituted arylisonitriles^[14] and thiophenols^[15] have far less offensive odors than the parent compounds.
• Very small molecules of similar shape, which seem most likely to be confused by a shape-based system, have extremely distinctive odors, such as hydrogen sulfide. However it has been suggested that metals such as Cu(I) may be associated with a metallo-receptor site in olfaction for strong-smelling volatiles which are also good metal-coordinating ligands, such as thiols.^[16] This hypothesis was confirmed in 2012 in the specific case of a thiol-responsive mouse olfactory receptor.^[17]
• Odor descriptions in the olfaction literature correlate more strongly with their vibrational frequencies than with their molecular shape.^[18]

See also

• Odotope theory
• Vibration theory of olfaction

References

1. Vosshall LB (2015). "Laying a controversial smell theory to rest". Proc. Natl. Acad. Sci. USA 112: 6525–6526. doi:10.1073/pnas.1507103112. PMID 26015552.
2. Moncrieff, Robert Wighton (1949), "What is odor? A new Theory", American Perfumer 54: 453
3. "The Nobel Prize in Physiology or Medicine 2004".
4. "Linda B. Buck, PhD - HHMI.org". HHMI.org.
5. Keller A, Vosshall LB (2004). "A psychophysical test of the vibration theory of olfaction". Nature Neuroscience 7: 337–338. doi:10.1038/nn1215. PMID 15034588.
6. "Testing a radical theory". Nat. Neurosci. 7: 315. 2004. doi:10.1038/nn0404-315. PMID 15048113.
7. TWOMBLY, RENEE (2004-03-26). "The Rockefeller University - Newswire: Two Rockefeller faculty become new HHMI investigators". Retrieved 2009-06-10.
8. Saberi M, Seyed-allaei (2015). "Olfactory receptors are sensitive to molecular volume of odorants". bioRxiv. doi:10.1101/013516.
9. Everts S (2015). "Receptor Research Reignites A Smelly Debate". Chem.& Eng. News 93 (18): 29–30.
10. Block E, et al. (2015). "Implausibility of the Vibrational Theory of Olfaction". Proc. Natl. Acad. Sci. USA 112 (21): E2766–E2774. doi:10.1073/pnas.1503054112. PMID 25901328.
11. Sell, CS (2006). "On the Unpredictability of Odor". Angew. Chem. Int. Ed. 45: 6254–6261. doi:10.1002/anie.200600782.
12. Turin L (1996). "A spectroscopic mechanism for primary olfactory reception". Chem. Senses 21 (6): 773–91. doi:10.1093/chemse/21.6.773. PMID 8985605.
13. Doszczak, L; Kraft, P; Weber, H-P; Bertermann, R; Triller, A; Hatt, H; Reinhold Tacke, R (2007). "Prediction of Perception: Probing the hOR17-4 Olfactory Receptor Model with Silicon Analogues of Bourgeonal and Lilial". Angew. Chem. Int. Ed. 46: 3367–3371. doi:10.1002/anie.200605002.
14. Pirrung, MC; Ghorai, S; Ibarra-Rivera, TR (2009). "Multicomponent Reactions of Convertible Isonitriles". J. Org. Chem. 74: 4110–4117. doi:10.1021/jo900414n. PMID 19408909.
15. Nishide, K; Miyamoto, T; Kumar, K; Ohsugi, S-I; Node, M (2002). "Synthetic equivalents of benzenethiol and benzyl mercaptan having faint smell: odor reducing effect of trialkylsilyl group". Tetrahedron Lett. 43: 8569–8573. doi:10.1016/s0040-4039(02)02052-x.
16. Crabtree, R.H. (1978). "Copper(I) – Possible Olfactory Binding-Site". J. Inorg. Nucl. Chem. 1978 (40): 1453. doi:10.1016/0022-1902(78)80071-2.
17. Duan, Xufang; Block, Eric; Li, Zhen; Connelly, Timothy; Zhang, Jian; Huang, Zhimin; Su, Xubo; Pan, Yi; Wu, Lifang; Chi, Qiuyi; Thomas, Siji; Zhang, Shaozhong; Ma, Minghong; Matsunami, Hiroaki; Chen, Guo-Qiang; Zhuang, Hanyi (2012). "Crucial role of copper in detection of metal-coordinating odorants". Proc. Natl. Acad. Sci. U.S.A 2012 (109): 3492–3497. Bibcode:2012PNAS..109.3492D. doi:10.1073/pnas.1111297109. PMC 3295281. PMID 22328155.
18. Takane SY, Mitchell JBO (2004). "A structure-odour relationship study using EVA descriptors and hierarchical clustering". Org. Biomol. Chem. 2 (22): 3250–5. doi:10.1039/B409802A. PMID 15534702.

• Burr, Chandler (2003). The Emperor of Scent: A Story of Perfume, Obsession, and the Last Mystery of the Senses. New York: Random House. ISBN 0-375-50797-3.
• Turin, Luca (2006). The Secret of Scent. London: Faber & Faber. ISBN 978-0-571-21537-9.
• Zozulya et al. (2001) "The human olfactory receptor repertoire."