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Docking theory of olfaction

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The docking theory of olfaction proposes that the smell of an odorant molecule is due to a range of weak non-covalent interactions between the odorant [a ligand] and its protein odorant receptor (found in the nasal epithelium), such as electrostatic and Van der Waals interactions as well as H-bonding, dipole attraction, pi-stacking, metal ion, Cation–pi interaction, and hydrophobic effects, in addition to odorant conformation.[1][2] While this type of recognition has previously been termed the shape theory of olfaction,[3] which primarily considers molecular shape and size, this latter model is oversimplified since two scent molecules may have similar shapes and sizes but different sets of weak intermolecular forces and therefore activate different combinations of odorant receptors. Earlier “lock and key” and "hand in glove" models of protein−ligand binding has been replaced by a more nuanced pictures which consider the distortion of flexible molecules so as to form the optimal interactions with binding partners as in molecular docking of non-olfactory G-protein coupled receptors.

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used Linus Pauling's notion of shape-based molecular interactions to propose a shape-based theory of odor.[4] This superseded the older vibration theory of olfaction, and, renamed the docking theory of olfaction to more accurately reflect a range of non-covalent interactions in addition to shape, 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.[5] 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.[6] Since all types of G-protein receptors currently known are activated through binding (docking) of molecules with highly specific conformations (shapes) and non-covalent interactions, it is assumed that olfactory receptors operate in a similar fashion. Further research on human olfaction systems identified 347 olfactory receptors.

A recent version of the previously named 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 the docking theory focuses on neural processing, rather than the specific interaction between odorant and receptor that generates the original signal.[7]

Support

Numerous studies have been conducted to elucidate the complex relationship between the docking 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.[8][9] The data were described by Vosshall as "consistent with the shape theory", although she added that "they don't prove the shape theory".[10]

Another study also showed that molecular volume of odorants can determine the upper limits of neural responses of olfactory receptors in Drosophila.[11]

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".[12] 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.[13] 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."[3] 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."[12]

Challenges

  • Despite numerous studies, docking theory has yet to discover structure-odor relations with great predictive power.[14]
  • Similarly shaped molecules with different molecular vibrations have different smells (metallocene experiment and deuterium replacement of molecular hydrogen).[15] In the metallocene experiment, Turin observes that while ferrocene and nickelocene have nearly the same molecular sandwich structures, they possess distinct odors. He suggests that "because of the change in size and mass, different metal atoms give different frequencies for those vibrations that involve the metal atoms,"[15] an observation which is compatible with the vibration theory. However it has been noted that, in contrast to ferrocene, nickelocene rapidly decomposes in air and the cycloalkene odor observed for nickelocene, but not for ferrocene, could simply reflect decomposition of nickelocene giving trace amounts of hydrocarbons such as cyclopentadiene.[2] The challenge regarding smell of molecules with similar structures 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,[16] with studies showing that the human musk receptor OR5AN1 responds identically to deuterated and non-deuterated musks[13] and with single-neuron comparison of the olfactory receptor response to deuterated and nondeuterated odorants.[17]
  • 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[18] and thiophenols[19] 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.[20][21] This hypothesis was confirmed in the specific cases of thiol-responsive mouse and human olfactory receptors.[22][23]
  • It is claimed that odor descriptions in the olfaction literature correlate more strongly with their vibrational frequencies than with their molecular shape.[24]

See also

References

  1. ^ Horsfield, A. P.; Haase, A.; Turin, L. (2017). "Molecular recognition in olfaction". Advances in Physics: X. 2 (3): 937–977. doi:10.1080/23746149.2017.1378594.
  2. ^ a b Block, E. (2018). "Molecular basis of mammalian odor discrimination: A status report". Journal of Agricultural and Food Chemistry. 66 (51): 13346–13366. doi:10.1021/acs.jafc.8b04471. PMID 30453735.
  3. ^ a b Vosshall LB (2015). "Laying a controversial smell theory to rest". Proc. Natl. Acad. Sci. USA. 112 (21): 6525–6526. Bibcode:2015PNAS..112.6525V. doi:10.1073/pnas.1507103112. PMC 4450429. PMID 26015552.
  4. ^ Moncrieff, Robert Wighton (1949), "What is odor? A new Theory", American Perfumer, 54: 453
  5. ^ Amoore JE (1952). "The stereochemical specificities of human olfactory receptors". Perfumery & Essential Oil Record. 43: 321–330.
  6. ^ "The Nobel Prize in Physiology or Medicine 2004".
  7. ^ "Linda B. Buck, PhD - HHMI.org". HHMI.org.
  8. ^ Keller A; Vosshall LB (2004). "A psychophysical test of the vibration theory of olfaction". Nature Neuroscience. 7 (4): 337–338. doi:10.1038/nn1215. PMID 15034588.
  9. ^ "Testing a radical theory". Nat. Neurosci. 7 (4): 315. 2004. doi:10.1038/nn0404-315. PMID 15048113.
  10. ^ TWOMBLY, RENEE (2004-03-26). "The Rockefeller University - Newswire: Two Rockefeller faculty become new HHMI investigators". Archived from the original on 2008-10-29. Retrieved 2009-06-10.
  11. ^ Saberi M, Seyed-allaei (2016). "Odorant receptors of Drosophila are sensitive to the molecular volume of odorants". Scientific Reports. 6: 25103. Bibcode:2016NatSR...625103S. doi:10.1038/srep25103. PMC 4844992. PMID 27112241.
  12. ^ a b Everts S (2015). "Receptor Research Reignites A Smelly Debate". Chem. Eng. News. 93 (18): 29–30.
  13. ^ a b Block E, et al. (2015). "Implausibility of the Vibrational Theory of Olfaction". Proc. Natl. Acad. Sci. USA. 112 (21): E2766–E2774. Bibcode:2015PNAS..112E2766B. doi:10.1073/pnas.1503054112. PMC 4450420. PMID 25901328.
  14. ^ Sell, CS (2006). "On the Unpredictability of Odor". Angew. Chem. Int. Ed. 45 (38): 6254–6261. doi:10.1002/anie.200600782. PMID 16983730.
  15. ^ a b 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.
  16. ^ 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 (18): 3367–3371. doi:10.1002/anie.200605002. PMID 17397127.
  17. ^ Na, M.; Liu, M. T.; Nguyen, M. Q.; Ryan, K. (2019). "Single-neuron comparison of the olfactory receptor response to deuterated and nondeuterated odorants". ACS Chem. Neurosci. 10 (1): 552–562. doi:10.1021/acschemneuro.8b00416. PMID 30343564.
  18. ^ Pirrung, MC; Ghorai, S; Ibarra-Rivera, TR (2009). "Multicomponent Reactions of Convertible Isonitriles". J. Org. Chem. 74 (11): 4110–4117. doi:10.1021/jo900414n. PMID 19408909.
  19. ^ 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 (47): 8569–8573. doi:10.1016/s0040-4039(02)02052-x.
  20. ^ 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.
  21. ^ Block, E.; Batista, V.S.; Matsunami, H.; Zhuang, H.; Ahmed, L. (2017). "The role of metals in mammalian olfaction of low molecular weight organosulfur compounds". Natural Product Reports. 34 (5): 529–557. doi:10.1039/c7np00016b. PMC 5542778. PMID 28471462.
  22. ^ 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. 109 (9): 3492–3497. Bibcode:2012PNAS..109.3492D. doi:10.1073/pnas.1111297109. PMC 3295281. PMID 22328155.
  23. ^ Li, S.; Ahmed, L.; Zhang, R.; Pan, Y.; Matsunami, H.; Burger, J. L.; Block, E.; Batista, V. S.; Zhuang, H. (2016). "Smelling sulfur: Copper and silver regulate the response of human odorant receptor OR2T11 to low molecular weight thiols". Journal of the American Chemical Society. 138 (40): 13281–13288. doi:10.1021/jacs.6b06983. PMID 27659093.
  24. ^ 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.

Further reading

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