Docking 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 [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. While this type of recognition has previously been termed the shape theory of olfaction, 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 Earlier “lock and key” and "hand in glove" models of protein−ligand binding has been replaced by a more nuanced pictures which consider the distortion of flexible molecules so as to form the optimal interactions with binding partners as in molecular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. This superseded the older vibration theory of olfaction, and, renamed the docking theory of olfaction to more accurately reflect a range of non-covalent interactions in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. 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. 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.
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. 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".<ref name="10.1101/013516"></ref>
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". 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 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 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."