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

5HT(2A)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(2A)R activation remain poorly understood. We utilized all-atom molecular dynamics simulations and free-energy calculations to investigate 5HT(2A)R's conformational dynamics upon binding to serotonin and psilocin. We show that the active state of 5HT(2A)R collapses to a closed state in the absence of Gq alpha, 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(2A)R's activation and may aid in developing novel therapeutics.