Translocation Mechanism of Allosteric Sodium Ions in β₂-Adrenoceptor

Abstract

The allosteric modulation of G-protein-coupled receptors (GPCRs) by sodium ions has received significant attention as the crystal structures of several receptors show the binding of sodium ions (Na + ) at the conserved D 2.50 . Theoretical studies have shown that extracellular Na + would enter the allosteric D 2.50 via the orthosteric site. However, it remains unclear how the bound allosteric Na + would leave the GPCRs. In this study, we performed molecular dynamics (MD) simulations to illustrate the energy barriers of Na + transfer through the transmembrane helix bundle of β 2 AR. In contrast to the postulations from other GPCRs, the translocation of this allosteric Na + into the intracellular side is found to be significantly difficult. Hence, the translocation direction could be receptor-specific.

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

“…8 In the past 20 years, simulations of membrane proteins have progressed from the picosecond timescale to simulations of a G protein-coupled receptor (GPCR) on the scale of tens of microseconds. 9 This dramatic increase in accessible timescale has enabled studies of the atomistic details of GPCR activation, 10 ion-membrane protein allostery, 11 and membrane protein-ligand binding pathways, 12 among others. Despite all of these advancements, a persistent challenge in modeling membranes is related to the intrinsic dielectric gradient that exists as a function of position along the membrane normal.…”

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

“…In the past 20 years, simulations of membrane proteins have progressed from the picosecond time scale to simulations of a G protein-coupled receptor (GPCR) on the scale of tens of microseconds . This dramatic increase in accessible time scale has enabled studies of the atomistic details of GPCR activation, ion-membrane protein allostery, and membrane protein–ligand binding pathways, among others.…”

“…8 In the past 20 years, simulations of membrane proteins have progressed from the picosecond time scale to simulations of a G protein-coupled receptor (GPCR) on the scale of tens of microseconds. 9 This dramatic increase in accessible time scale has enabled studies of the atomistic details of GPCR activation, 10 ion-membrane protein allostery, 11 and membrane protein−ligand binding pathways, 12 among others. Despite all of these advancements, a persistent challenge in modeling membranes is related to the intrinsic dielectric gradient that exists as a function of position along the membrane normal.…”