Neuroreceptor Activation by Vibration-Assisted Tunneling

TL;DR

This study explores a quantum chemical model suggesting that vibrationally assisted electron tunneling activates GPCRs, with potential implications for drug design and understanding receptor activation mechanisms.

Contribution

It applies inelastic electron tunneling spectroscopy to GPCR activation, proposing a vibrational mechanism validated by spectral analysis and theoretical predictions.

Findings

Serotonin receptor agonists share a specific IET spectral peak.

Peak intensity correlates with known agonist potencies.

Model predicts spectral features for deuterated compounds.

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 hypothesis 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.