Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study

[Image: see text] We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX(2) receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-m...

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Autores principales: Karhu, Lasse, Magarkar, Aniket, Bunker, Alex, Xhaard, Henri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727383/
https://www.ncbi.nlm.nih.gov/pubmed/30786708
http://dx.doi.org/10.1021/acs.jpcb.8b10220
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author Karhu, Lasse
Magarkar, Aniket
Bunker, Alex
Xhaard, Henri
author_facet Karhu, Lasse
Magarkar, Aniket
Bunker, Alex
Xhaard, Henri
author_sort Karhu, Lasse
collection PubMed
description [Image: see text] We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX(2) receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol–POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.
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spelling pubmed-67273832019-09-06 Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study Karhu, Lasse Magarkar, Aniket Bunker, Alex Xhaard, Henri J Phys Chem B [Image: see text] We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX(2) receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol–POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state. American Chemical Society 2019-02-20 2019-03-28 /pmc/articles/PMC6727383/ /pubmed/30786708 http://dx.doi.org/10.1021/acs.jpcb.8b10220 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Karhu, Lasse
Magarkar, Aniket
Bunker, Alex
Xhaard, Henri
Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title_full Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title_fullStr Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title_full_unstemmed Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title_short Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
title_sort determinants of orexin receptor binding and activation—a molecular dynamics study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727383/
https://www.ncbi.nlm.nih.gov/pubmed/30786708
http://dx.doi.org/10.1021/acs.jpcb.8b10220
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