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1 Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China, 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, 3 School of Pharmacy, East China University of Science and Technology, Shanghai, China, 4 UNESCO Chair of Biophysics & Molecular Neurobiology and Instituto de Investigaciones Bioquímicas de Bahía Blanca, Bahía Blanca, Argentina
The nicotinic acetylcholine receptor (nAChR) is a key molecule involved in the propagation of signals in the central nervous system and peripheral synapses. Although numerous computational and experimental studies have been performed on this receptor, the structural dynamics of the receptor underlying the gating mechanism is still unclear. To address the mechanical fundamentals of nAChR gating, both conventional molecular dynamics (CMD) and steered rotation molecular dynamics (SRMD) simulations have been conducted on the cryo-electron microscopy (cryo-EM) structure of nAChR embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer and water molecules. A 30-ns CMD simulation revealed a collective motion amongst C-loops, M1, and M2 helices. The inward movement of C-loops accompanying the shrinking of acetylcholine (ACh) binding pockets induced an inward and upward motion of the outer β-sheet composed of β9 and β10 strands, which in turn causes M1 and M2 to undergo anticlockwise motions around the pore axis. Rotational motion of the entire receptor around the pore axis and twisting motions among extracellular (EC), transmembrane (TM), and intracellular MA domains were also detected by the CMD simulation. Moreover, M2 helices undergo a local twisting motion synthesized by their bending vibration and rotation. The hinge of either twisting motion or bending vibration is located at the middle of M2, possibly the gate of the receptor. A complementary twisting-to-open motion throughout the receptor was detected by a normal mode analysis (NMA). To mimic the pulsive action of ACh binding, nonequilibrium MD simulations were performed by using the SRMD method developed in one of our laboratories. The result confirmed all the motions derived from the CMD simulation and NMA. In addition, the SRMD simulation indicated that the channel may undergo an open-close (O 
C) motion. The present MD simulations explore the structural dynamics of the receptor under its gating process and provide a new insight into the gating mechanism of nAChR at the atomic level.
Figure 2.Collective Motions of the C-Loops, M1, and M2 Helices
(A) The time-dependence of the volumes of ACh binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.
(B) The motion tendencies of C-loops, M1, and M2 reflected by the superposition of subunit α1 at the beginning (green) and after 30 ns simulation (cyan). The picture is displayed parallel to the pore axis.
(C–D) The anticlockwise motions of the M1 and M2 helices. The superpositions are based on the centers of mass of the five M1 and M2 helices, respectively, and the pictures are viewed from the synaptic cleft.
From: Mechanics of Channel Gating of the Nicotinic Acetylcholine Receptor Liu X, Xu Y, Li H, Wang X, Jiang H, et al. PLoS Computational Biology Vol. 4, No. 1, e19 doi:10.1371/journal.pcbi.0040019
