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.
Highlights
G Protein-Coupled Receptors (GPCRs), called seven-pass-transmembrane domain receptors, are a large family of membrane-bound eukaryotic proteins
We demonstrate below that this is the case by verifying that the well-tempered metadynamics calculations achieve convergence, that the free energy landscapes smoothly span the conformational space corresponding to thestable at https://submission.gpcrmd.org/view/213/ (APO), lysergic acid diethylamide (LSD), and LIS structures, and that the structural changes in key motifs that are indicative of receptor activation are consistent with experimental reports
We conducted enhanced sampling molecular dynamics simulations using well-tempered metadynamics to estimate the conformational free energy surfaces for the 5-HT2B-TM seratonin receptor in the unliganded (APO system), LSD-bound (LSD system), and lisuride-bound (LIS system) states. Comparison of these free energy landscapes, each of which is parameterized by the root mean squared deviation (RMSD) of the orthosteric binding pocket (OBP) residues relative to the lisuride-bound and LSD-bound systems (RMSDLIS, RMSDLSD), provide a quantitative measure of the perturbation to the conformational free energy landscape of the receptor induced by ligand binding, the driving force for conformational rearrangement of the ligand-receptor complex, and new molecular-level understanding for ligand-induced conformational specificity and functional selectivity
Summary
G Protein-Coupled Receptors (GPCRs), called seven-pass-transmembrane domain receptors, are a large family of membrane-bound eukaryotic proteins. These proteins undergo conformational change in response to the binding of extracellular drugs or ligands that results in receptor activation, intracellular G-protein recruitment, and downstream signaling [1,2,3].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
