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

Summary

The study investigates how ligand binding affects the conformational states of the GPCR serotonin receptor 5-HT2B. LSD binding induces a significant driving force of approximately 110 kJ/mol for the receptor to adopt an active state, while the lisuride-bound form is only about 24 kJ/mol more stable than the unliganded form. This research provides insights into ligand-induced conformational changes and offers a basis for virtual screening of ligands and engineering of the receptor's free energy landscape.

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.