ABSTRACT
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 in a physiological environment revealed that external stimulus is propagated to the intracellular surface of the receptor through subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. To amend the widely accepted theory we suggest 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.
ABBREVIATIONS
- GPCR
- G protein-coupled receptor
- TM6
- 6th transmembrane helix
- ICL1
- 1st intracellular loop
- H8
- cytosolic helix
- MD
- molecular dynamics
- EM2
- endomorphin-2
- TM
- transmembrane
- GTP
- guanosine-triphosphate
- ICL3
- 3rd intracellular loop
- NVT
- constant number of particles, volume and temperature
- NPT
- constant number of particles, pressure and temperature
- RMSD
- root mean square deviation
- DCCM
- dynamic cross-correlation matrix
- MI
- mutual information
- ICL2
- 2nd intracellular loop
- TM7
- 7th transmembrane helix
- Vm
- transmembrane electrostatic potential