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

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