Abstract
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.
Highlights
The nicotinic acetylcholine receptor is a key molecule involved in the propagation of signals between nerve cells and their targets at the central nervous system and peripheral synapses
As a paradigm of the ligand-gated ion channels (LGICs) superfamily, nicotinic acetylcholine receptor (nAChR) is a member of the Cysloop family which includes the 5-hydroxytryptamine type 3 (5-HT3) receptor, c-aminobutyric acid type A (GABAA) and GABAC receptors, and glycine receptors [1]. nAChRs have been identified as crucial elements in central nervous system functions such as consciousness, attention, and memory; and participate in numerous cerebral circuits
Using conventional molecular dynamics (CMD), normal mode analysis, and nonequilibrium MD techniques, we investigated the mechanical fundamentals of nAChR gating
Summary
The nicotinic acetylcholine receptor (nAChR) is a key molecule involved in the propagation of signals between nerve cells and their targets at the central nervous system and peripheral synapses. The nAChR has a special place in the history of ion channels since it has scored a number of ‘‘firsts’’: it was the first ion channel to be purified, to be sequenced, to be functionally reconstituted in synthetic lipid bilayers, to be cloned, and to be recorded the electrical signal as a single open channel [11]. It is the only ligand-gated channel to have an experimentally determined three-dimensional structure [12]. This physiologically and pharmacologically important receptor has been used as a model for studying the structure–function relationship of the ligandgated ion channels [1,5,6,12]
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