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

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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 organization: Division of Pharmaceutical Chemistry and Technology
Division of Pharmaceutical Biosciences
Drug Research Program
Pharmaceutical biophysics group
Pharmaceutical Design and Discovery group
Henri Xhaard / Principal Investigator
Date: 2019-03-28
Language: eng
Number of pages: 14
Belongs to series: Journal of Physical Chemistry B
ISSN: 1520-6106
DOI: https://doi.org/10.1021/acs.jpcb.8b10220
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
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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