Molecular Dynamics of μ Opioid Receptor Complexes with Agonists and Antagonists

Opioid receptors like other G-protein-coupled receptors undergo specific rearrangements of structure upon activation by agonists. Such processes proceed via several steps ruled by different molecular switches. In order to reveal the first steps of receptor activation concurrent with ligand binding, we investigated μ opioid receptor complexes with antagonists naltrexone and -FNA, and two closely related agonists morphine and N-methyl-morphine. The molecular dynamics simulations revealed distinct binding modes of analyzed antagonists and agonists. They all interacted with D3.32 on TM3 but while the antagonists formed a bond with Y3.33 (TM3) the agonists bound H6.52 (TM6). Furthermore, it was possible to observe a break of a hydrogen bond D3.32-Y7.43 between TM3 and TM7 (3-7 lock) during simulations of agonist complexes but not those of antagonist. Interdependence between the 3-7 lock and the rotamer toggle switch of W6.48 is proposed based on simulation of the naltrexone complex restrained to force an agonistic action.