TY - JOUR T1 - Atomic-Level Characterization of the Methadone-Stabilized Active Conformation of µ-Opioid Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.119.119339 SP - mol.119.119339 AU - Abhijeet Kapoor AU - Davide Provasi AU - Marta Filizola Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/07/17/mol.119.119339.abstract N2 - Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classical opioids, in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of β-arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classical opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes is unknown. Here, we report the results of sub-millisecond adaptive sampling molecular dynamics (MD) simulations of a predicted methadone-bound MOR complex, and compare them with analogous data obtained for the classical opioid morphine and the G protein-biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov State Models (MSMs) and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR.SIGNIFICANCE STATEMENT Opioid addiction has reached epidemic proportions in both industrialized and developing countries. Although methadone maintainance treatment represents an effective therapeutic approach for opioid addiction, it is not widely used as needed. In this study, we contribute an atomic-level understanding of how methadone exerts its unique function, in pursuit of more accessible treatments for opioid addiction. In particular, we present details of a methadone-specific active conformation of the µ-opioid receptor that has thus far eluded experimental structural characterization. ER -