Agonist-Specific Conformations of the M2 Muscarinic Acetylcholine Receptor Assessed by Molecular Dynamics.

Journal of Chemical Information and Modeling
Alena RandákováJ Jakubík

Abstract

Binding of muscarinic ligands, both antagonists and agonists, and their effects on the conformation of the M2 acetylcholine receptor were modeled in silico and compared to experimental data. After docking of antagonists to the M2 receptor in an inactive conformation (3UON, 5ZK3, 5ZKB, or 5ZKB) and agonists in an active conformation (4MQS), 100 ns of conventional molecular dynamics (MD) followed by 500 ns of accelerated MD was run. Conventional MD revealed ligand-specific interactions with the receptor. Antagonists stabilized the receptor in an inactive conformation during accelerated MD. The receptor in complex with various agonists attained different conformations specific to individual agonists. The magnitude of the TM6 movement correlated with agonist efficacy at the non-preferential Gs pathway. The shape of the intracellular opening where the receptor interacts with a G-protein was different for the classical agonist carbachol, super-agonist iperoxo, and Gi/o-biased partial agonists JR-6 and JR-7, being compatible with experimentally observed agonist bias at the G-protein level. Moreover, a wash-resistant binding of the unique agonist xanomeline associated with interactions with membrane lipids was formed during accelerated...Continue Reading

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Citations

May 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Alena Randáková, Jan Jakubík

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