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
b-sheet composed of b9 and b10 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.