Neuroreceptor Activation by Vibration-Assisted Tunneling

Hoehn, Ross D.; Nichols, David E.; Neven, Hartmut; Kais, Sabre

doi:10.1038/srep09990

Cited by 18 publications

(36 citation statements)

References 64 publications

(73 reference statements)

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“…This peak was consistent with the works of Chee and June (33), Chee et al (34), and Oh (35), who attempted to generate a novel pharmacophore tool based on shared vibrational peaks. From the candidate deuteration schemes discussed above, we sought the greatest possible alteration in efficacy at the previously suggested activation peak to focus our experimental effort (36).…”

Section: Resultsmentioning

confidence: 99%

“…Turin-within the contemporary VTO-hypothesized that the active site of the GPCR [specifically an OR, although later works considered generalizing this hypothesis (18,36,58)] acts as an ET junction (11). According to the theory, an electron emerges from a donation site-likely a metal atom acting as a cofactor (11,31), redox chemistry (59), or peptide sidechain (11,60) capable of oxidation-and traverses the active site to an acceptor site, which is likely a specific motif or residue sidechain.…”

Section: Theoretical Predictionsmentioning

confidence: 99%

“…Within this previous study, tunneling spectra were generated and a single common peak among all of the agonists was determined; the IET probability density displayed behavior scaling with the efficacies of the agonists at the 5HT2A receptor (36). Herein, we test the validity of this vibrational theory of protein activation by examining the assumed active peak-as determined in the above-discussed previous work (36)-at roughly 1,500-1,650 cm −1 ; this energy range is also in agreement with a characteristic infrared peak for histidine receptors as determined by Chee and June (33), Chee et al (34), and Oh (35).…”

Section: Theoretical Predictionsmentioning

confidence: 99%

“…Initial justifications of the VTO correlated characteristics of the vibrational spectra with olfactory perception (12), continued within ORs (32), and expanded into non-OR GPCRs (33)(34)(35)(36). Isotope exchange-which provides the ability to alter the vibrations of a molecule while maintaining its chemistry-may manifest itself as an alteration of either the intensity or the quality of the scent.…”

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confidence: 99%

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Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Hoehn

Nichols

McCorvy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recently, an alternative theory concerning the method by which olfactory proteins are activated has garnered attention. This theory proposes that the activation of olfactory G protein-coupled receptors occurs by an inelastic electron tunneling mechanism that is mediated through the presence of an agonist with an appropriate vibrational state to accept the inelastic portion of the tunneling electron's energy. In a recent series of papers, some suggestive theoretical evidence has been offered that this theory may be applied to nonolfactory G protein- O lfaction-and other chemo-sensitive sensory processes-is an important information-gathering technique for organisms of many clades and kingdoms. Specifically, human olfaction is known to occur by activation of olfactory receptors (ORs)-a subclass of G protein-coupled receptors (GPCRs)-located within the nasal epithelium and mediating responses within the olfactory bulb, where it is encoded and conveys information to the amygdala, the orbitofrontal cortex, and the hippocampus (1, 2). The discovery and the cloning of ORs led to the joint 2004 Nobel Prize in Physiology and Medicine to Richard Axel and Linda Buck. (3) GPCRs are 7-helical transmembrane proteins, facilitating communication from extracellular ligand signals to the cellular interior through activation of (interior) G proteins, while maintaining the integrity of the membrane (4). GPCRs are activated by an appropriate agonist moving into the protein's orthosteric binding site, resulting in a conformational change within the helical bundle. This structural change leads to altered conformations of the intracellular loops that couple to appropriate signaling molecules within the cell, e.g., G proteins. A recent series of papers has experimentally determined activated/inactivated states through isotopic-tagged receptors with NMR spectroscopy (5-7). An additional work used molecular dynamics to provide structural insights into how the agonist may assist the interchange between conformations through several proposed peptide sidechain pathways by examining the structures of the activated and inactivated µ-opioid receptor (8). Additionally, photon-induced conformational changes in lightsensitive proteins have also been observed (9, 10).Recently, an iteration of the vibrational theory of olfaction (VTO)-suggested and advocated by Luca Turin (11, 12)-has arisen and has gained both supporters (13-16) and detractors (17, 18); the novelty of this incarnation of the VTO is ascribable to its nonthermal-and nonphoton-based mechanism. Turin's theory is a contemporary reincarnation of the more classical theory proposed by Dyson (19), Wright (20), and Wright and Serenius (21), where the activation of the olfactory receptor is performed-or sensitive to-the molecular vibrations of the olfactant. Dyson suggested that the molecular vibrations of the agonist were exactly responsible for the activation of the protein. These vibrations were entirely thermally excited, as no mechanism for photoexcitation is available within the body. Th...

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Section: Resultsmentioning

confidence: 99%

Section: Theoretical Predictionsmentioning

confidence: 99%

Section: Theoretical Predictionsmentioning

confidence: 99%

mentioning

confidence: 99%

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Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Hoehn

Nichols

McCorvy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Calculating the electronic coupling for initial and final wave functions without any structural information would constitute very involved guess-work, given structural fluctuations on the picosecond time scale and sub-ångström distances may substantially affect any quantum process. However, recent studies have advanced knowledge of the binding site [50] and new research is emerging to show that biological IETS may play a role in neuroreceptors [51]. So let the notion of phonon-assisted electron tunnelling (as a signalling mechanism) be emphasized and not ignored, if not a role in olfaction, but perhaps in other systems in biology that rely upon ligand-receptor activation.…”

Section: (A) Challenges and Future Prospectsmentioning

confidence: 99%

Quantum effects in biology: golden rule in enzymes, olfaction, photosynthesis and magnetodetection

Brookes

2017

Proc. R. Soc. A.

101

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Despite certain quantum concepts, such as superposition states, entanglement, 'spooky action at a distance' and tunnelling through insulating walls, being somewhat counterintuitive, they are no doubt extremely useful constructs in theoretical and experimental physics. More uncertain, however, is whether or not these concepts are fundamental to biology and living processes. Of course, at the fundamental level all things are quantum, because all things are built from the quantized states and rules that govern atoms. But when does the quantum mechanical toolkit become the best tool for the job? This review looks at four areas of 'quantum effects in biology'. These are biosystems that are very diverse in detail but possess some commonality. They are all (i) effects in biology: rates of a signal (or information) that can be calculated from a form of the 'golden rule' and (ii) they are all protein-pigment (or ligand) complex systems. It is shown, beginning with the rate equation, that all these systems may contain some degree of quantum effect, and where experimental evidence is available, it is explored to determine how the quantum analysis aids in understanding of the process.

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The complexities of ligand/receptor interactions: Exploring the role of molecular vibrations and quantum tunnelling

Pagán

2024

BioEssays

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Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels.

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Neuroreceptor Activation by Vibration-Assisted Tunneling

Cited by 18 publications

References 64 publications

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Quantum effects in biology: golden rule in enzymes, olfaction, photosynthesis and magnetodetection

The complexities of ligand/receptor interactions: Exploring the role of molecular vibrations and quantum tunnelling

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