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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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