Pharmacologically Distinct Ligands Induce Different States of 5-HT2AR and Trigger Different Membrane Remodeling: Implications For GPCR Oligomerization

Abstract

We report on microsecond-scale molecular dynamics simulations of ligand-bound serotonin 2A receptor (5-HT2AR), which demonstrate for the first time at atomic detail how ligands with different measurable effects trigger differential structural perturbations both in the GPCR and the surrounding membrane. In these simulations the full agonist (5-HT), partial agonist (LSD) and inverse agonist (Ketanserin) affect differently the GPCR structural motifs/functional microdomains (e.g., the toggle switch and the ionic lock), stabilizing different conformational states of 5-HT2AR. We find that the dynamics of 5-HT in the binding pocket, moving away from and reentering the binding pocket, are correlated with the dynamics of the ionic lock which prefers the activated state configuration when the agonist is bound. Notably, significant conformational changes occur when 5-HT is replaced by Ketanserin in the activated state, resulting in the stabilization of an inactive-like state of the receptor, consonant with the inverse agonist properties of the ligand. The different states of GPCRs induced by pharmacologically distinct ligands also induce different reorganizations of the lipid matrix surrounding the receptor, and the local membrane perturbations produce different extents of hydrophobic mismatch around the transmembrane (TM) helices of 5-HT2AR. We quantified the energetics of these perturbations with a novel computational procedure (see Sayan Mondal et al., this meeting) for quantitative modeling of anisotropic bilayer deformations around multi-helical TM insertions. To our knowledge, this is the first calculation of differences in membrane remodeling by a GPCR in complex with different ligands, establishing a link between the receptor response to different ligands and the specific membrane deformations. The mechanistic implications of these results point to modes of ligand-induced GPCR oligomerization driven by the hydrophobic mismatch between the receptor and the membrane.