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Neuroreceptor Activation by Vibration-Assisted Tunneling

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submitted on 2024-09-12, 08:40 and posted on 2024-09-12, 08:43 authored by Ross D. Hoehn, David Nichols, Hartmut Neven, Sabre Kais

G protein-coupled receptors (GPCRs) constitute a large family of receptor proteinsthat sense molecular signals on the exterior of a cell and activate signaltransduction pathways within the cell. Modeling how an agonist activates such areceptor is fundamental for an understanding of a wide variety of physiologicalprocesses and it is of tremendous value for pharmacology and drug design. Inelasticelectron tunneling spectroscopy (IETS) has been proposed as a model for themechanism by which olfactory GPCRs are activated by a bound agonist. We apply thishyothesis to GPCRs within the mammalian nervous system using quantum chemicalmodeling. We found that non-endogenous agonists of the serotonin receptor share aparticular IET spectral aspect both amongst each other and with the serotoninmolecule: a peak whose intensity scales with the known agonist potencies. We proposean experiential validation of this model by utilizing lysergic acid dimethylamide(DAM-57), an ergot derivative and its deuterated isotopologues; we also providetheoretical predictions for comparison to experiment. If validated our theory mayprovide new avenues for guided drug design and elevate methods of in silicopotency/activity prediction.

Other Information

Published in: Scientific Reports
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1038/srep09990

Funding

NSF Centers for Chemical Innovation: QuantumInformation for Quantum Chemistry (CHE-1037992).

History

Language

  • English

Publisher

Springer Nature

Publication Year

  • 2015

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • Qatar Environment and Energy Research Institute - HBKU