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Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches
Article

The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation

1
Institute for Medical Physics and Biophysics, University of Leipzig, Härtelstr. 16-18, D-04107 Leipzig, Germany
2
Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Brüderstr. 34, D-04103 Leipzig, Germany
3
Vanderbilt University Medical Center, 2200 Pierce Avenue, Nashville, TN 37232, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Berlin Joint Electron Paramagnetic Resonance Laboratory, Free University Berlin, 14195 Berlin, Germany.
Academic Editor: Oliver Zerbe
Molecules 2020, 25(23), 5489; https://doi.org/10.3390/molecules25235489
Received: 16 October 2020 / Revised: 9 November 2020 / Accepted: 12 November 2020 / Published: 24 November 2020
We report data on the structural dynamics of the neuropeptide Y (NPY) G-protein-coupled receptor (GPCR) type 1 (Y1R), a typical representative of class A peptide ligand GPCRs, using a combination of solid-state NMR and molecular dynamics (MD) simulation. First, the equilibrium dynamics of Y1R were studied using 15N-NMR and quantitative determination of 1H-13C order parameters through the measurement of dipolar couplings in separated-local-field NMR experiments. Order parameters reporting the amplitudes of the molecular motions of the C-H bond vectors of Y1R in DMPC membranes are 0.57 for the Cα sites and lower in the side chains (0.37 for the CH2 and 0.18 for the CH3 groups). Different NMR excitation schemes identify relatively rigid and also dynamic segments of the molecule. In monounsaturated membranes composed of longer lipid chains, Y1R is more rigid, attributed to a higher hydrophobic thickness of the lipid membrane. The presence of an antagonist or NPY has little influence on the amplitude of motions, whereas the addition of agonist and arrestin led to a pronounced rigidization. To investigate Y1R dynamics with site resolution, we conducted extensive all-atom MD simulations of the apo and antagonist-bound state. In each state, three replicas with a length of 20 μs (with one exception, where the trajectory length was 10 μs) were conducted. In these simulations, order parameters of each residue were determined and showed high values in the transmembrane helices, whereas the loops and termini exhibit much lower order. The extracellular helix segments undergo larger amplitude motions than their intracellular counterparts, whereas the opposite is observed for the loops, Helix 8, and termini. Only minor differences in order were observed between the apo and antagonist-bound state, whereas the time scale of the motions is shorter for the apo state. Although these relatively fast motions occurring with correlation times of ns up to a few µs have no direct relevance for receptor activation, it is believed that they represent the prerequisite for larger conformational transitions in proteins. View Full-Text
Keywords: GPCR; arrestin; molecular switch; NMR spectroscopy; structural dynamics; MD simulation GPCR; arrestin; molecular switch; NMR spectroscopy; structural dynamics; MD simulation
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MDPI and ACS Style

Vogel, A.; Bosse, M.; Gauglitz, M.; Wistuba, S.; Schmidt, P.; Kaiser, A.; Gurevich, V.V.; Beck-Sickinger, A.G.; Hildebrand, P.W.; Huster, D. The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation. Molecules 2020, 25, 5489. https://doi.org/10.3390/molecules25235489

AMA Style

Vogel A, Bosse M, Gauglitz M, Wistuba S, Schmidt P, Kaiser A, Gurevich VV, Beck-Sickinger AG, Hildebrand PW, Huster D. The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation. Molecules. 2020; 25(23):5489. https://doi.org/10.3390/molecules25235489

Chicago/Turabian Style

Vogel, Alexander, Mathias Bosse, Marcel Gauglitz, Sarah Wistuba, Peter Schmidt, Anette Kaiser, Vsevolod V. Gurevich, Annette G. Beck-Sickinger, Peter W. Hildebrand, and Daniel Huster. 2020. "The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation" Molecules 25, no. 23: 5489. https://doi.org/10.3390/molecules25235489

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