Molecular dynamics of fentanyl bound to -opioid receptor

The molecular dynamics simulations of fentanyl complexed with the -opioid receptor (OR) were studied using both inactive 4DKL and active 5C1M opioid receptor crystal structures. Analogous simulations in morphine with or without a ligand were done for comparison. Simulations of the inactive states were carried out in the absence and presence of the Na+ ion. The obtained fentanyl's binding mode agrees with some of the mutagenesis data, and it overlaps with that of morphine only to a minor extent. Notably, fentanyl stabilizes different rotameric states of Trp293(6.48) than observed for morphine or unliganded receptor. Another difference is tighter arrangement of the interaction between Asp147(3.32) and Tyr326(7.43) (a link between helices TM3 and TM7) in the presence of fentanyl. Principal component analysis reveals differences in the trajectories dependent on the ligand bound. The differences found could be linked to ligand-dependent efficacy with respect to receptor intracellular signaling events.