κ-Opioid Receptor Model in a Phospholipid Bilayer: Molecular Dynamics Simulation

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Abstract
A three-dimensional molecular model of the transmembrane domain of the κ-opioid receptor in a phospholipid bilayer is presented. The endogenous ligand, dynorphin A (1), and synthetic ligands, benzomorphan-based compounds (2a, 2b) (Figure 1), are docked into the model. We report the results of a 500 ps molecular dynamics simulation of these protein−ligand complexes in a simplified bilayer of 97 molecules of the lipid dipalmitoylphosphatidylcholine and 26 water molecules per lipid. The simulations explore the stability and conformational dynamics of the model in a phospholipid bilayer; we also investigate the interactions of the protein with its ligands. Molecular simulation of the receptor−ligand complexes, endogenous and synthetic, has confirmed the existence of different binding domains for peptide and non-peptide ligands. Similarities are found in the dynamics and binding mode of all conformations of the synthetic ligands studied. The protonated hydrogen of the benzomorphan is always involved in an H-bond with Asp138, and other potentially stabilizing receptor−ligand interactions found involve the hydroxyl substituent on the benzomorphan, which may form an H-bond with Tyr139 or Gly190 according to the different molecules. The ester group of 2a may therefore form an H-bond with Ile316, while the carbonyl group of 2b forms an H-bond with Gln115 and Tyr312. The remaining part of the ligand is located in the extracellular portion of the pocket. It is surrounded by hydrophobic residues in the transmembrane region (TM), and it interacts with different sets of residues. The results obtained are in general agreement with site-directed mutagenesis data that have highlighted the importance of all TM regions for synthetic-ligand affinity with the κ-opioid receptor.