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

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.