Lessons from free energy simulations of δ-opioid receptor homodimers involving the fourth transmembrane helix

Several G protein-coupled receptors (GPCRs), including opioid receptors δOR, μOR, and κOR, have been reported to form stable dimers or oligomers in lipid bilayers and cell membranes. This notion has been recently challenged by imaging data supporting a transient nature of GPCR association. Here we use umbrella sampling reconstructed free energies of δOR homodimers involving the fourth transmembrane helix to predict their association constant. The results of these simulations, combined with estimates of diffusion-limited association rates, suggest a short lifetime for δOR homodimers in the membrane, in agreement with recent trends.