The continuing debate over the basis of odorant recognition with respect to the molecular shape (“lock and key”) theory versus the vibrational theory could potentially be resolved by the testing of 13C-labeled odorants. The application of 13C isotopomers is discussed herein by means of DFT-calculated IR vibrations and Gibbs’ free energies (Δ ) for acetophenone and octan-1-ol, two odorants for which the 2D (deuterium) isotopomers have previously been shown to be discernible from their respective 1H (normal) counterparts by Drosophila melanogaster. 1. Introduction For many animals, their ability to detect volatile molecules-odorants-by way of the olfactory sense can literally mean the difference between survival and demise or the continued propagation of the species. By contrast, for human beings, our sense of smell, which is weak in comparison to some animals, is considered more of an indulgence rather than a functionality necessary for survival on a par with sight and hearing, perhaps thereby explaining in part, from an anthropocentric perspective, why it is the least understood of our senses. Although olfactory receptor (OR) sites have been identified and the molecular basis for the olfactory sensory process elucidated (both in vertebrates and insects for which the processes differ [1])—indeed, the work warranted the awarding of a Nobel Prize to Buck and Axel [2–4] for this outstanding accomplishment—the means by which odorants are recognized at the molecular level and actuation occurs is still debated. Thus, intriguingly, despite numerous attempts and decades of endeavor, there is still no definitive consensus on the identity of the molecular property that the OR is responding to, and the manner of odorant recognition remains, surprisingly, a contentious issue [5–15]. Overall, there are, or have been over the years, a number of competing theories, either distinct or modified, and these theories or variations thereof number in the dozens [6, 15, 16]. It is, however, generally accepted [1, 6, 15, 17] presently by mainstream researchers that the molecular basis for odorant recognition by an OR is essentially based on the molecular size and shape (the “fit”) of the odorant originating from the work of Moncrieff [16, 18] and then further solidified by Amoore [16, 19, 20]. The concept is generally referred to as the shape or “lock and key” theory (in addition to various permutations). An alternate theory that is nonetheless prominent, and somewhat controversial (e.g., [12]), is the vibrational theory whereby odorant recognition is considered to be based on
References
[1]
U. B. Kaupp, “Olfactory signalling in vertebrates and insects: differences and commonalities,” Nature Reviews Neuroscience, vol. 11, no. 3, pp. 188–200, 2010.
[2]
L. Buck and R. Axel, “A novel multigene family may encode odorant receptors: a molecular basis for odor recognition,” Cell, vol. 65, no. 1, pp. 175–187, 1991.
[3]
R. Axel, “Scents and sensibility: a molecular logic of olfactory perception (Nobel Lecture),” Angewandte Chemie, vol. 44, no. 38, pp. 6111–6127, 2005.
[4]
L. B. Buck, “Unraveling the sense of smell (Nobel Lecture),” Angewandte Chemie, vol. 44, no. 38, pp. 6128–6140, 2005.
[5]
R. C. Araneda, A. D. Kini, and S. Firestein, “The molecular receptive range of an odorant receptor,” Nature Neuroscience, vol. 3, no. 12, pp. 1248–1255, 2000.
[6]
U. J. Meierhenrich, J. Golebiowski, X. Fernandez, and D. Cabrol-Bass, “The molecular basis of olfactory chemoreception,” Angewandte Chemie, vol. 43, no. 47, pp. 6410–6412, 2004.
[7]
S. Gane, D. Georganakis, K. Maniati et al., “Molecular vibration-sensing component in human olfaction,” PLoS ONE, vol. 8, no. 1, Article ID e55780, 2013.
[8]
A. Keller and L. B. Vosshall, “A psychophysical test of the vibration theory of olfaction,” Nature Neuroscience, vol. 7, no. 4, pp. 337–338, 2004.
[9]
L. J. W. Haffenden, V. A. Yaylayan, and J. Fortin, “Investigation of vibrational theory of olfaction with variously labelled benzaldehydes,” Food Chemistry, vol. 73, no. 1, pp. 67–72, 2001.
[10]
M. I. Franco, L. Turin, A. Mershin, and E. M. C. Skoulakis, “Reply to Hettinger: olfaction is a physical and a chemical sense in Drosophila,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 31, p. E350, 2011.
[11]
M. I. Franco, L. Turin, A. Mershin, and E. M. C. Skoulakis, “Molecular vibration-sensing component in Drosophila melanogaster olfaction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 9, pp. 3797–3802, 2011.
[12]
T. P. Hettinger, “Olfaction is a chemical sense, not a spectral sense,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 31, p. E349, 2011.
[13]
J. C. Brookes, A. P. Horsfield, and A. M. Stoneham, “Odour character differences for enantiomers correlate with molecular flexibility,” Journal of the Royal Society Interface, vol. 6, no. 30, pp. 75–86, 2009.
[14]
J. C. Brookes, F. Hartoutsiou, A. P. Horsfield, and A. M. Stoneham, “Could humans recognize odor by phonon assisted tunneling?” Physical Review Letters, vol. 98, no. 3, Article ID 038101, 2007.
[15]
C. S. Sell, “On the unpredictability of odor,” Angewandte Chemie, vol. 45, no. 38, pp. 6254–6261, 2006.
[16]
H. L. Klopping, “Olfactory theories and the odors of small molecules,” Journal of Agricultural and Food Chemistry, vol. 19, no. 5, pp. 999–1004, 1971.
[17]
S.-y. Takane and J. B. O. Mitchell, “Structure—odour relationship study using EVA descriptors and hierarchical clustering,” Organic & Biomolecular Chemistry, vol. 2, no. 22, pp. 3250–3255, 2004.
[18]
R. W. Moncrieff, The Chemical Senses, Leonard Hill, London, UK, 2nd edition, 1951.
[19]
J. E. Amoore, Molecular Basis of Odor, Thomas CC, Springfield, Ill, USA, 1970.
[20]
J. E. Amoore, “Stereochemical theory of olfaction,” Nature, vol. 198, no. 4877, pp. 271–272, 1963.
[21]
G. M. Dyson, “The scientific basis of odor,” Chemistry & Industry, vol. 57, pp. 647–651, 1938.
[22]
R. H. Wright, “Odor and chemical constitution,” Nature, vol. 173, no. 4409, pp. 831–831, 1954.
[23]
R. H. Wright, “Odor and molecular vibration,” Nature, vol. 190, no. 4781, pp. 1101–1102, 1961.
[24]
R. H. Wright, “Stereochemical and vibrational theories of odour,” Nature, vol. 239, no. 5369, pp. 226–226, 1972.
[25]
K. Buijs, C. J. H. Schutte, and F. Verster, “Absence of correlation between odour and molecular vibration,” Nature, vol. 192, no. 4804, pp. 751–752, 1961.
[26]
L. Turin, “A spectroscopic mechanism for primary olfactory reception,” Chemical Senses, vol. 21, no. 6, pp. 773–791, 1996.
[27]
I. A. Solov'yov, P. Y. Chang, and K. Schulten, “Vibrationally assisted electron transfer mechanism of olfaction: myth or reality?” Physical Chemistry Chemical Physics, vol. 14, no. 40, pp. 13861–13871, 2012.
[28]
L. B. Buck, “The molecular architecture of odor and pheromone sensing in mammals,” Cell, vol. 100, no. 6, pp. 611–618, 2000.
[29]
S. Firestein, “How the olfactory system makes sense of scents,” Nature, vol. 413, no. 6852, pp. 211–218, 2001.
[30]
B. D. Rubin and L. C. Katz, “Spatial coding of enantiomers in the rat olfactory bulb,” Nature Neuroscience, vol. 4, no. 4, pp. 355–356, 2001.
[31]
H. J. Bestmann and C. Rehefeld, “Pheromones. 68. Electrophysiological studies with deuterated pheromones—evidence of an isotope effect,” Naturwissenschaften, vol. 76, no. 9, pp. 422–424, 1989.
[32]
J. Hara, “Olfactory discrimination between glycine and deuterated glycine by fish,” Experientia, vol. 33, no. 5, pp. 618–619, 1977.
[33]
J. E. Amoore, “Stereochemical and vibrational theories of odour,” Nature, vol. 233, no. 5317, pp. 270–271, 1971.
[34]
P. Weyerstahl, “Odor and structure,” Journal für Praktische Chemie/Chemiker-Zeitung, vol. 336, no. 2, pp. 95–109, 1994.
[35]
R. M. Carman and K. D. Klika, “Partially racemic compounds as brushtail possum urinary metabolites,” Australian Journal of Chemistry, vol. 45, no. 4, pp. 651–657, 1992.
[36]
M. Spehr, G. Gisselmann, A. Poplawski et al., “Identification of a testicular odorant receptor mediating human sperm chemotaxis,” Science, vol. 299, no. 5615, pp. 2054–2058, 2003.
[37]
T. Hanada, M. Kashiwayanagi, and K. Kurihara, “Temperature increase abolishes ability of turtle olfactory receptors to discriminate similar odorant,” American Journal of Physiology, vol. 266, no. 6, pp. R1816–R1823, 1994.
[38]
M. G. J. Beets, “Structure and odor,” S.C.I. Monograph, vol. 1, no. 1, pp. 54–90, 1957.
[39]
M. J. Frisch, G. W. Trucks, H. B. Schlegel et al., Gaussian 09, Revision A. 01, Gaussian, Wallingford, Conn, USA, 2009.
[40]
K. D. Klika, P. T？htinen, P. M？nts？l？, J. Niemi, and M. Mets？-Ketel？, “The potential of VCD to resolve the epimer vs. inverse epimer quandary,” Computational and Theoretical Chemistry, vol. 992, pp. 156–163, 2012.
[41]
Y. Zhao and D. G. Truhlar, “The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals,” Theoretical Chemistry Accounts, vol. 120, no. 1–3, pp. 215–241, 2008.
[42]
Y. Zhao and D. G. Truhlar, “Density functionals with broad applicability in chemistry,” Accounts of Chemical Research, vol. 41, no. 2, pp. 157–167, 2008.
