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

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http://hdl.handle.net/10138/301182

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Karhu , L , Magarkar , A , Bunker , A & Xhaard , H 2019 , ' Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study ' , Journal of Physical Chemistry B , vol. 123 , no. 12 , pp. 2609-2622 . https://doi.org/10.1021/acs.jpcb.8b10220

Title: Determinants of Orexin Receptor Binding and Activation—A Molecular Dynamics Study
Author: Karhu, Lasse; Magarkar, Aniket; Bunker, Alex; Xhaard, Henri
Contributor: University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
Date: 2019-03-28
Language: eng
Number of pages: 14
Belongs to series: Journal of Physical Chemistry B
ISSN: 1520-6106
URI: http://hdl.handle.net/10138/301182
Abstract: We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX2 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.
Subject: 116 Chemical sciences
PROTEIN-COUPLED RECEPTOR
GUI MEMBRANE-BUILDER
STRUCTURAL BASIS
ALLOSTERIC MODULATION
FORCE-FIELD
MODEL
OX1
CHOLESTEROL
MECHANISM
PEPTIDES
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