Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor.

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.

Study at a glance

Abstract

G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.