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Neuroreceptor activation by vibration-assisted tunneling - PubMed

  • ️Thu Jan 01 2015

Neuroreceptor activation by vibration-assisted tunneling

Ross D Hoehn et al. Sci Rep. 2015.

Abstract

G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hyothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction.

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Figures

Figure 1
Figure 1. The tunneling spectrum of several known 5-HT2A agonists as well as the square of the tunneling PDF reflected below the energy axes; the square is used to highlight major spectral aspects.

The Spectral Similarity Index of each plot is given in the Supplemental Materials over several ranges and regions, noting that these similarity indices allude to good spectral agreement with the reference spectrum, LSD. More detailed information is provided within the Supplemental Material.

Figure 2
Figure 2. (a) The tunneling spectra of several DOX class agonists as well as their molecular structures. (b) The inverse of the median effective concentration for the DOX class agonists plotted against the tunneling probability within the region at 1500 ± 35 cm−1. The trend of tunneling intensity follows roughly the trend of the agonist’s potency at the 5-HT2A receptor.
Figure 3
Figure 3. (a) The tunneling spectra of several 2C-X class agonists as well as their molecular structures. (b) The inverse of the median effective concentration for the 2C-X class agonists plotted against the tunneling probability within the region at 1500 ± 35 cm−1. The trend of tunneling intensity follows roughly the trend of the agonist’s potency at the 5-HT2A receptor.
Figure 4
Figure 4. The tunneling spectrum of several deuterium-isotopologues of DAM-57.

Yellow highlights have been given to the energy region which is assumed to be the active energy region for inelastic tunneling transfer. Specific deuterations deplete the tunneling probability within this region, and may effectively eliminate the agonism of the molecule within the 5-HT2A receptor.

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References

    1. Arndt J. T., Vedral M. & Vedral V. Quantum physics meets biology. HFSP. J. 3, 386 (2009). - PMC - PubMed
    1. Davies P. C. W. Does quantum mechanics play a non-trivial role in life? BioSystems 78, 69 (2004). - PubMed
    1. Ball P. The dawn of quantum biology. Nature 474, 272 (2011). - PubMed
    1. Huelga S. F. & Plenio M. B. Vibriations, Quanta and Biology. Contemporary Physics 54, 181 (2013).
    1. Lloyd S., Mohseni M., Shabani A. & Rabitz H. The quantum Goldilocks effect: on the convergence of timescales in quantum transport. . arXiv:1111.4982 [quant-ph] (2011).

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