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 classic 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 classic 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 are unknown. Here, we report the results of submillisecond adaptive sampling molecular dynamics simulations of a predicted methadone-bound MOR complex and compare them with analogous data obtained for the classic opioid morphine and the G protein–biased ligand TRV130. The model, which is supported by existing experimental data, is analyzed using Markov state models and transfer entropy analysis to provide testable hypotheses of methadone-specific conformational dynamics and activation kinetics of MOR.

中文翻译：

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µ-阿片受体美沙酮稳定活性构象的原子水平表征。

美沙酮是一种合成阿片类激动剂，具有众所周知的独特特性，例如较低的滥用可能性以及诱导缓解戒断症状和药物渴望，尽管美沙酮作用于经典阿片类药物触发的相同阿片受体，特别是 µ-阿片受体 (MOR)。其独特的药理学特性最近被归因于β-抑制蛋白相对于 G 蛋白的优先激活，使美沙酮成为阿片类药物成瘾的标准护理维持药物。尽管最近的一项生物物理学研究表明，美沙酮稳定的 MOR 活性构象与经典阿片类药物或 G 蛋白偏向激动剂稳定的 MOR 活性构象不同，但这种药物如何调节 MOR 的构象平衡以及它稳定的受体的特定活性构象尚不清楚。在这里，我们报告了预测的美沙酮结合 MOR 复合物的亚毫秒自适应采样分子动力学模拟结果，并将其与经典阿片类吗啡和 G 蛋白偏向配体 TRV130 获得的类似数据进行比较。该模型得到现有实验数据的支持，并使用马尔可夫状态模型和转移熵分析进行分析，以提供美沙酮特异性构象动力学和 MOR 激活动力学的可检验假设。