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

By Lasse Karhu (3107445), Aniket Magarkar (606769), Alex Bunker (606775) and Henri Xhaard (467313)


We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX<sub>2</sub> 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

Topics: Biophysics, Biochemistry, Medicine, Cell Biology, Genetics, Molecular Biology, Neuroscience, Pharmacology, Sociology, Cancer, Computational Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, unliganded receptor, orexin receptor activation, small-molecular ligands, binding modes, POPC membrane, neuropeptide orexin-A, binding mode, Orexin Receptor Binding, OX 2 receptor, activation determinants, dynamics simulations, antagonist suvorexant, agonist Nag 26, 36 μ
Year: 2019
DOI identifier: 10.1021/acs.jpcb.8b10220.s002
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Provided by: FigShare
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