Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

Abstract

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.

Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

“…Thus, the interaction of the (1)-6-OH-7-Cl-PAT 6-OH moiety with S5.46 was crucial for its binding, whereas this amino acid hardly impacted binding of (2)-6-OH-7-Cl-PAT. This observation is unusual compared with most other 5-HT2A-targeting compounds reported (Almaula et al, 1996a;Braden and Nichols, 2007;Shan et al, 2012), including DOI. For example, of more than 20 compounds tested, only the ergot derivatives, e.g., ergonovine, showed major losses in affinity at the human S5.46A 5-HT2A receptor (Almaula et al, 1996a;Braden and Nichols, 2007).…”

Graded activation and free energy landscapes of a muscarinic G-protein–coupled receptor

“…In earlier computational studies, ligand-dependent dynamics of GPCRs were investigated using the cMD (7,10), metadynamics (8,9), and aMD (11) methods. Whereas cMD simulations revealed distinct conformational changes in several known GPCR activation elements (7), these simulations lasting several hundred nanoseconds were not long enough to capture the entire GPCR activation/ deactivation processes.…”

“…The structure, dynamics, and function of GPCRs result from underlying free energy landscapes (4). However, quantitative characterization of the GPCR activation and ligand-dependent free energy profiles has proved challenging (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

“…Although these crystal structures provided enormously important insights into different specific conformational states, as well as atomistic protein-ligand interactions of GPCRs, they nonetheless represent snapshots of the highly dynamic nature of GPCRs (20). To address the above issue, extensive computational simulations have been performed to characterize the structural dynamics of GPCRs (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). All-atom molecular dynamics (MD) simulations are capable of exploring large-scale conformational changes during both receptor activation (23) and deactivation (20) by using fast supercomputers.…”