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

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Item Type:Article
Title:Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations.
Creators Name:Meral, D., Provasi, D., Prada-Gracia, D., Möller, J., Marino, K., Lohse, M.J. and Filizola, M.
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.
Keywords:Cell Membrane, Cholesterol, Kinetics, Lipid Bilayers, Molecular Dynamics Simulation, Phosphatidylcholines, Protein Conformation, Protein Multimerization, mu Opioid Receptors
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group
Volume:8
Number:1
Page Range:7705
Date:16 May 2018
Official Publication:https://doi.org/10.1038/s41598-018-26070-8
PubMed:View item in PubMed

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