The 5HT2AR receptor, a G-protein-coupled receptor targeted by psychedelic drugs, collapses to a closed active state without Gqα, revealing an intermediate partially-open conformation. Molecular dynamics simulations and free-energy calculations show that serotonin and psilocin bind more tightly to the orthosteric pocket than to the extended binding pocket. These findings clarify activation mechanisms and may guide development of novel therapeutics for neurological and psychiatric disorders.
Psilocin, the active form of psilocybin in magic mushrooms, binds more strongly to the serotonin 2A receptor (5-HT2AR) than the natural hormone serotonin does. Using molecular dynamics simulations and free energy calculations, the authors show that this higher binding affinity is due to psilocin's tertiary amine group, not the different position of its hydroxyl group. The binding strength depends on the protonation states of both psilocin and a key receptor residue, aspartate 155. These molecular insights suggest design rules for developing more effective antidepressants.