Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties
Figure 2
Structures of ligands with different efficacy and their interactions with 5-HT2AR during MD simulations.
(A) Chemical structures of 5-HT, LSD and KET. Amines interacting with D3.32, S3.36 or S5.46 [6], [7], [116], [117], [118], [119] are labeled. (B,C,D) Docking poses in the initial structures (left panels) and during the simulations (right panels) for 5-HT (B), LSD (C) and KET (D), respectively. For clarity, only TM 3, 5 and 6 are shown in grey ribbons. Sidechains of residues D3.32, S3.36, S5.43, S5.46, F5.47, F6.44, W6.48, F6.51, F6.52 and N6.55 are depicted as sticks, and 5-HT (carbons colored in orange), LSD (cyan) and KET (green) are rendered in spheres. Note that, due to its large-size, and because its quinazoline ring penetrates deep into the binding pocket close to W6.48, KET is in direct contact with all the residues in the aromatic cluster, including F5.47. (E) Time-evolution of backbone TM RMSDs of 5-HT2AR (upper panel) and of the distances between the carboxyl/hydroxyl oxygens in D3.32, S3.36 and S5.46 on 5-HT2AR and their interacting amine nitrogens on ligands (see panel A) during the simulations (lower panels). Traces are shown in orange for 5-HT, in cyan for LSD, and in green for KET. Data were collected every 100 ps. Running averages were calculated every 10 data points and are shown in bold shades. Nα atom of 5-HT maintains a salt-bridge with D3.32 and forms an H-bond with S3.36 (Figure S2 in Text S1); N1 atom of 5-HT forms an H-bond with S5.46 either directly or through a water-bridge.