Molecular insights into the modulation of the 5HT<sub>2A</sub> receptor by serotonin, psilocin, and the G protein subunit Gqα.
Abstract
5HT<sub>2A</sub>R is a G-protein-coupled receptor that drives many neuronal functions and is a target for psychedelic drugs. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT<sub>2A</sub>R activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT<sub>2A</sub>R's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT<sub>2A</sub>R collapses to a closed state in the absence of Gqα, underscoring the importance of G-protein coupling. We discover an intermediate "partially-open" receptor conformation. Both ligands have higher binding affinities for the orthosteric than the extended binding pocket. These findings enhance our understanding of 5HT<sub>2A</sub>R's activation and may aid in developing novel therapeutics. Impact statement This study sheds light on 5HT<sub>2A</sub>R activation, revealing intermediate conformations and ligand dynamics. These insights could enhance drug development for neurological and psychiatric disorders, benefiting researchers and clinicians in pharmacology and neuroscience.
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