Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations

Sci Rep. 2018 May 16;8(1):7705. doi: 10.1038/s41598-018-26070-8.


Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Membrane / metabolism*
  • Cholesterol / metabolism*
  • Humans
  • Kinetics
  • Lipid Bilayers / metabolism*
  • Molecular Dynamics Simulation
  • Phosphatidylcholines / metabolism*
  • Protein Conformation
  • Protein Multimerization*
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / metabolism*


  • Lipid Bilayers
  • Phosphatidylcholines
  • Receptors, Opioid, mu
  • Cholesterol