Understanding the activation mechanism of the μ-opioid receptor (μ-OR) and its selective coupling to the inhibitory G protein (G_i) is vital for pharmaceutical research aimed at finding treatments for the opioid overdose crisis. Many attempts have been made to understand the mechanism of the μ-OR activation, following the elucidation of new crystal structures such as the antagonist- and agonist-bound μ-OR. However, the focus has not been placed on the underlying energetics and specificity of the activation process. An energy-based picture would not only help to explain this coupling but also help to explore why other possible options are not common. For example, one would like to understand why μ-OR is more selective to G_i than a stimulatory G protein (G_s). Our study used homology modeling and a coarse-grained model to generate all of the possible “end states” of the thermodynamic cycle of the activation of μ-OR. The end points were further used to generate reasonable intermediate structures of the receptor and the G_i to calculate two-dimensional free energy landscapes. The results of the landscape calculations helped to propose a plausible sequence of conformational changes in the μ-OR and G_i system and for exploring the path that leads to its activation. Furthermore, in silico alanine scanning calculations of the last 21 residues of the C terminals of G_i and G_s were performed to shed light on the selective binding of G_i to μ-OR. Overall, the present work appears to demonstrate the potential of multiscale modeling in exploring the action of G protein-coupled receptors.

了解 μ-阿片受体 (μ-OR) 的激活机制及其与抑制性 G 蛋白 (G _i ) 的选择性偶联对于旨在寻找阿片类药物过量危机治疗方法的药物研究至关重要。在阐明了新的晶体结构（例如拮抗剂和激动剂结合的μ-OR）之后，人们进行了许多尝试来了解μ-OR激活的机制。然而，焦点尚未放在激活过程的潜在能量学和特异性上。基于能量的图像不仅有助于解释这种耦合，还有助于探索为什么其他可能的选择不常见。例如，人们想了解为什么 μ-OR 对 G _i比刺激性 G 蛋白 (G _s ) 更具选择性。我们的研究使用同源建模和粗粒度模型来生成 μ-OR 激活的热力学循环的所有可能的“最终状态”。端点进一步用于生成受体和 G _i的合理中间结构，以计算二维自由能景观。景观计算的结果有助于提出 μ-OR 和 G _i系统中构象变化的合理序列，并有助于探索导致其激活的路径。此外，对G _i和G _s C 末端的最后21 个残基进行计算机丙氨酸扫描计算，以揭示G _i与μ-OR 的选择性结合。总体而言，目前的工作似乎证明了多尺度建模在探索 G 蛋白偶联受体作用方面的潜力。