期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：42
页码：26218-26225
DOI：10.1073/pnas.2013364117
出版社：The National Academy of Sciences of the United States of America
摘要：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.
