Shape 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 ligandand one or more G protein-coupled
odorant receptors Olfactory receptors (ORs), also known as odorant receptors, are chemoreceptors expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (for example, compounds that have an odor) which give ri ...
(found in the
nasal Nasal is an adjective referring to the nose, part of human or animal anatomy. It may also be shorthand for the following uses in combination: * With reference to the human nose: ** Nasal administration, a method of pharmaceutical drug delivery ** ...
epithelium Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
). These include intermolecular forces, such as dipole-dipole and Van der Waals interactions, as well as hydrogen bonding. More specific proposed interactions include metal-ion, ion-ion, cation-pi and
pi-stacking In chemistry, pi stacking (also called π–π stacking) refers to the presumptive attractive, noncovalent pi interactions (molecular orbital, orbital overlap) between the pi bonds of aromaticity, aromatic rings. However this is a misleading des ...
. Interactions can be influenced by the hydrophobic effect. Conformational changes can also have a significant impact on interactions with receptors, as ligands have been shown to interact with ligands without being in their conformation of lowest energy. While this theory of odorant recognition has previously been described as the
shape theory of olfaction 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 ligandand one or more G protein-coupled odorant receptors (found in the nasal epithelium). The ...
, which primarily considers molecular shape and size, this earlier model is oversimplified, since two odorants may have similar shapes and sizes but are subject to different intermolecular forces and therefore activate different combinations of
odorant receptors Olfactory receptors (ORs), also known as odorant receptors, are chemoreceptors expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (for example, compounds that have an odor) which give ri ...
, allowing them to be distinguished as different smells by the brain. Other names for the model, such as “lock and key” and "hand in glove", are also misnomers: there are only 396 unique olfactory receptors and too many distinguishable smells for a one-to-one correlation between an odorant and a receptor. Since olfactory receptors have not yet been successfully crystalized, the docking theory of olfaction relies on the known properties of other G protein-coupled receptors that have been crystalized, as well as structural predictions given the known primary structure, to produce a likely olfactory receptor model. Though olfactory receptors are similar to other G protein-coupled receptors, there are notable differences in the primary structure that make exact comparisons unfeasible. Because of this, predicted olfactory receptor structures have been aided by the development of new structure-predicting softwares. From this data, simpler odorant-receptor binding models have been developed into more nuanced ideas which consider the distortion of flexible molecules so as to form optimal interactions with binding partners. These modifications help the model to conform better to what is known of the
molecular docking In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex. Knowledge of the preferred orientation in tu ...
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 Linus Carl Pauling (; February 28, 1901August 19, 1994) was an American chemist, biochemist, chemical engineer, peace activist, author, and educator. He published more than 1,200 papers and books, of which about 850 dealt with scientific top ...
's notion of shape-based molecular interactions to propose a shape-based theory of odor. This superseded the older
vibration theory of olfaction The vibration theory of smell proposes that a molecule's smell character is due to its vibrational frequency in the infrared range. This controversial theory is an alternative to the more widely accepted docking theory of olfaction (formerly termed ...
, 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. 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 Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel ('' Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...
, cyclooctane, and
naphthalene Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08  ppm by mass. As an aromati ...
could bind. When
Linda Buck Linda Brown Buck (born January 29, 1947) is an American biologist best known for her work on the olfactory system. She was awarded the 2004 Nobel Prize in Physiology or Medicine, along with Richard Axel, for their work on olfactory receptors. She ...
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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
used for olfaction. 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 Odotope theory, also known as weak shape theory, is a theory of how olfactory receptors bind to odor molecules. The theory proposes that a combination of shape factors determine the coupling. The word itself is an analogy to epitope An epitope, al ...
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.


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 Leslie Birgit Vosshall (born July 5, 1965) is an American neurobiologist and currently an Howard Hughes Medical Institute (HHMI) Investigator and the Robin Chemers Neustein Professor of Neurogenetics and Behavior at The Rockefeller University. ...
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. The data were described by Vosshall as "consistent with the shape theory", although she added that "they don't prove the shape theory". Another study also showed that molecular volume of odorants can determine the upper limits of neural responses of olfactory receptors in ''Drosophila''. 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 receptor Olfactory receptors (ORs), also known as odorant receptors, are chemoreceptors expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (for example, compounds that have an odor) which give ri ...
s 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". 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. 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 Isotopomers or isotopic isomers are isomers with isotopic atoms, having the same number of each isotope of each element but differing in their positions. The result is that the molecules are either constitutional isomers or stereoisomers solely ...
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." 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 cell Human embryonic kidney 293 cells, also often referred to as HEK 293, HEK-293, 293 cells, or less precisely as HEK cells, are a specific immortalised cell line derived from a spontaneously miscarried or aborted fetus or human embryonic kidney cells ...
s doesn't adequately reconstitute the complex nature of
olfaction The sense of smell, or olfaction, is the special sense through which smells (or odors) are perceived. The sense of smell has many functions, including detecting desirable foods, hazards, and pheromones, and plays a role in taste. In humans, it ...
..." 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."


Challenges

*Despite numerous studies, docking theory has yet to discover structure-odor relations with great predictive power. *Similarly shaped molecules with different molecular vibrations have different smells ( metallocene experiment and deuterium replacement of molecular hydrogen). 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," 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. 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, with studies showing that the human musk receptor OR5AN1 responds identically to deuterated and non-deuterated musks and with single-neuron comparison of the olfactory receptor response to deuterated and nondeuterated odorants. *Differently shaped molecules with similar molecular vibrations have similar smells (replacement of carbon double bonds by
sulfur Sulfur (or sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula ...
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 and thiophenols 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 Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is poisonous, corrosive, and flammable, with trace amounts in ambient atmosphere having a characteristic foul odor of rotten eggs. The unde ...
. 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. This hypothesis was confirmed in the specific cases of thiol-responsive mouse and human olfactory receptors. *It is claimed that odor descriptions in the olfaction literature correlate more strongly with their vibrational frequencies than with their molecular shape.


See also

*
Odotope theory Odotope theory, also known as weak shape theory, is a theory of how olfactory receptors bind to odor molecules. The theory proposes that a combination of shape factors determine the coupling. The word itself is an analogy to epitope An epitope, al ...
*
Vibration theory of olfaction The vibration theory of smell proposes that a molecule's smell character is due to its vibrational frequency in the infrared range. This controversial theory is an alternative to the more widely accepted docking theory of olfaction (formerly termed ...


References


Further reading

* * *{{cite journal, last1=Zozulya , first1=Sergey, first2= Fernando , last2=Echeverri , first3= Trieu , last3=Nguyen , year=2001, title=The human olfactory receptor repertoire, journal=Genome Biology, volume=2, issue=6, pages=research0018.1, doi=10.1186/gb-2001-2-6-research0018, pmid=11423007, pmc=33394, doi-access=free Olfactory system 1949 introductions Theories