Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor.
PLoS ONE March 4, 2021 Brandon L Peters, Jinxia Deng, Andrew L Ferguson 4 citations
G protein-coupled receptors (GPCRs) change shape when a ligand binds, which determines whether they activate or block signaling inside cells. Using computer simulations, the free energy landscapes of the serotonin receptor 5-HT2B were calculated for its unbound form, bound to the agonist LSD, and bound to the antagonist lisuride. LSD binding provided a strong driving force of about 110 kJ/mol toward the active conformation, while lisuride binding stabilized the receptor only about 24 kJ/mol more than the unbound form and kept it structurally similar. The work quantifies how different ligands induce distinct conformational changes and functional selectivity, offering a platform for virtual drug screening and rational design of ligand effects.