Recent advancements in the field of experimental structural biology have provided
high-resolution structures of active and inactive state G protein-coupled receptors
(GPCRs), a highly important pharmaceutical target family, but the process of transition
between these states is poorly understood. According to the current theory, GPCRs
exist in structurally distinct, dynamically interconverting functional states of which
populations are shifted upon binding of ligands and intracellular signaling proteins.
However, explanation of the activation mechanism, on an entirely structural basis,
gets complicated when multiple activation pathways and active receptor states are
considered. Our unbiased, atomistic molecular dynamics simulations of the mu opioid
receptor (MOP) revealed that transmission of external stimulus to the intracellular
surface of the receptor is accompanied by subtle, concerted movements of highly conserved
polar amino acid side chains along the 7th transmembrane helix. This may entail the
rearrangement of polar species and the shift of macroscopic polarization in the transmembrane
domain, triggered by agonist binding. Based on our observations and numerous independent
indications, we suggest amending the widely accepted theory that the initiation event
of GPCR activation is the shift of macroscopic polarization between the ortho- and
allosteric binding pockets and the intracellular G protein-binding interface.
