Molecular insights into the modulation of the 5HT2A receptor by serotonin, psilocin, and the G protein subunit Gqα.

Abstract

5HT_2AR 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_2AR activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT_2AR's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT_2AR 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_2AR's activation and may aid in developing novel therapeutics. Impact statement This study sheds light on 5HT_2AR 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.