Molecular insights into the modulation of the 5HT_2Areceptor by serotonin, psilocin, and the G protein subunit Gqα

The 5HT_2Areceptor (5HT_2AR) is a G protein-coupled receptor that drives many neuronal functions and is one of the primary targets for psychedelic drugs, which have recently shown promise in treating mental disorders. Understanding ligand interactions and conformational transitions is essential for developing effective pharmaceuticals, but mechanistic details of 5HT_2AR activation and ligand binding modes remain poorly understood. We conducted all-atom molecular dynamics simulations and free energy calculations of the active and inactive forms of 5HT_2AR with psilocin and serotonin. Both serotonin and psilocin have higher binding affinities for the orthosteric binding pocket than the extended binding pocket. Active state 5HT_2AR collapses to a closed state in the absence of Gqα. We also discover a ‘partially-open’ receptor conformation that is intermediate between the active and inactive states. Our discoveries can inform the design of new pharmaceuticals that target specific receptor conformations, potentially leading to more effective treatments for mental disorders.