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

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

Author information

1
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
3
Institute of Pharmacology and Toxicology, Würzburg, Germany.
4
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. marta.filizola@mssm.edu.

Abstract

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.

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