TY  - JOUR
A1  - Meral, Derya
A1  - Provasi, Davide
A1  - Prada-Gracia, Diego
A1  - Möller, Jan
A1  - Marino, Kristen
A1  - Lohse, Martin J.
A1  - Filizola, Marta
T1  - Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations
T2  - Scientific Reports
N2  - 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.
KW  - computational biophysics
KW  - fluorescence resonance energy transfer
Y1  - 2018
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/22399
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-223995
VL  - 8
ER  -