Global InformationDocking theory of olfaction information
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 one or more G protein-coupled odorant receptors (found in the nasal epithelium). These include intermolecular forces, such as dipole-dipole and Van der Waals interactions, as well as hydrogen bonding.[1][2] More specific proposed interactions include metal-ion, ion-ion, cation-pi and pi-stacking. 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.[3]
While this theory of odorant recognition has previously been described as the shape theory of olfaction,[4] 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, 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.[2]
In a seminal paper published in 2023 in Nature which is consistent with the above description of the docking theory, Billesbølle and coworkers use cryo-electron microscopy to determine for the first time the structure of a human OR activated by an odorant, namely OR51E2 activated by propionate. The authors indicate that "propionate binds in a small cavity in OR51E2 that is completely occluded from the external solvent. It binds through two types of contact — specific ionic and hydrogen bonds, and non-specific hydrophobic contacts." Because of the specific shape of the binding pocket, OR51E2 is said to be specific for propionate and "does not bind to fatty acids with longer carbon chains."[5][6]
The docking theory of olfaction previously relied 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.[1] Though olfactory receptors are similar to other G protein-coupled receptors, there are notable differences in the primary structure that make exact comparisons unfeasible.[7] Because of this, predicted olfactory receptor structures have been aided by the development of new structure-predicting softwares.[8] 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 of non-olfactory G-protein coupled receptors.
- ^ a b Horsfield, A. P.; Haase, A.; Turin, L. (2017). "Molecular Recognition in olfaction". Advances in Physics: X. 2 (3): 937–977. Bibcode:2017AdPhX...2..937H. doi:10.1080/23746149.2017.1378594. hdl:11572/187885 – via ebscohost.
- ^ a b Cite error: The named reference
PMID 30453735was invoked but never defined (see the help page). - ^ Sell, Charles S. (2014). Chemistry of the sense of smell. Hoboken, New Jersey: John Wiley and Sonsa. pp. 392–393. ISBN 9780470551301.
- ^ Cite error: The named reference
Vosshallwas invoked but never defined (see the help page). - ^ Nature https://doi.org/10.1038/d41586-023-00439-w (2022).
- ^ Nature https://doi.org/10.1038/s41586-023-05798-y (2023).
- ^ Breer, Heinz (2003). "Olfactory receptors: molecular basis for recognition and discrimination of odors". Analytical and Bioanalytical Chemistry. 377 (3): 427–433. doi:10.1007/s00216-003-2113-9. PMID 12898108. S2CID 38188327 – via PubMed.
- ^ Yang, Yuedong; Gao, Jianzhao; Wang, Jihua; Heffernan, Rhys; Hanson, Jack; Paliwal, Kuldip; Zhou, Yaoqi (2018). "Sixty-five years of the long march in protein secondary structure prediction: the final stretch?". Briefings in Bioinformatics. 19 (3): 482–494. doi:10.1093/bib/bbw129. PMC 5952956. PMID 28040746.