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Mechanics of channel gating of the nicotinic acetylcholine receptor.

Liu X, Xu Y, Li H, Wang X, Jiang H, Barrantes FJ - PLoS Comput. Biol. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.

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 beta-sheet composed of beta9 and beta10 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.

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Dynamics of the M2 Helices(A) Bending vibrations of the M2 helices represented by changes of inclination angle along the CMD trajectory.(B) Schematic representation for the positions of some important residues throughout the M2 helices (left). Rotation angle profiles of the important residues (right).(C) Rotations of the L- and V-rings. The anticlockwise rotations of L- and V-rings are represented by the conformational superposition between the starting structure (green) and final structure of the CMD simulation (cyan) on the receptor.
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pcbi-0040019-g005: Dynamics of the M2 Helices(A) Bending vibrations of the M2 helices represented by changes of inclination angle along the CMD trajectory.(B) Schematic representation for the positions of some important residues throughout the M2 helices (left). Rotation angle profiles of the important residues (right).(C) Rotations of the L- and V-rings. The anticlockwise rotations of L- and V-rings are represented by the conformational superposition between the starting structure (green) and final structure of the CMD simulation (cyan) on the receptor.

Mentions: Figure 4B indicates that M2 helices possibly engage in a bending motion in addition to rotation. Indeed, inspection of the conformational changes in M2 helices along the CMD trajectory revealed a significant bending motion. Although previous studies have also detected the bending motion of M2 helices [34], our 30-ns CMD simulation provides more detailed information. For each M2 helix, the bending hinge is located between L251 and V255. Thus, the pore channel is divided into two parts by the hinge. We describe the bending of each M2 helix by the inclination angle of the top part of the helix with respect to the bottom part, as illustrated in Figure 5A. The inclination angle profiles indicate that each M2 helix undergoes a bending vibration, and the amplitude of α1M2 helix is the largest (Figure 5A). A recent single-molecule kinetic analysis on αM2 of nAChR suggested that most of the residues throughout the length of αM2 move relatively early in the gating reaction, but some at the mid-section move later [26]. This experimental result implies that the mid-section moves slower than the other part does, i.e., the αM2 might bend round the hinge during the gating process. This result gave an indirect support to the bending vibration of M2 helices, especially α1M2, as detected by our CMD simulation.


Mechanics of channel gating of the nicotinic acetylcholine receptor.

Liu X, Xu Y, Li H, Wang X, Jiang H, Barrantes FJ - PLoS Comput. Biol. (2008)

Dynamics of the M2 Helices(A) Bending vibrations of the M2 helices represented by changes of inclination angle along the CMD trajectory.(B) Schematic representation for the positions of some important residues throughout the M2 helices (left). Rotation angle profiles of the important residues (right).(C) Rotations of the L- and V-rings. The anticlockwise rotations of L- and V-rings are represented by the conformational superposition between the starting structure (green) and final structure of the CMD simulation (cyan) on the receptor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211534&req=5

pcbi-0040019-g005: Dynamics of the M2 Helices(A) Bending vibrations of the M2 helices represented by changes of inclination angle along the CMD trajectory.(B) Schematic representation for the positions of some important residues throughout the M2 helices (left). Rotation angle profiles of the important residues (right).(C) Rotations of the L- and V-rings. The anticlockwise rotations of L- and V-rings are represented by the conformational superposition between the starting structure (green) and final structure of the CMD simulation (cyan) on the receptor.
Mentions: Figure 4B indicates that M2 helices possibly engage in a bending motion in addition to rotation. Indeed, inspection of the conformational changes in M2 helices along the CMD trajectory revealed a significant bending motion. Although previous studies have also detected the bending motion of M2 helices [34], our 30-ns CMD simulation provides more detailed information. For each M2 helix, the bending hinge is located between L251 and V255. Thus, the pore channel is divided into two parts by the hinge. We describe the bending of each M2 helix by the inclination angle of the top part of the helix with respect to the bottom part, as illustrated in Figure 5A. The inclination angle profiles indicate that each M2 helix undergoes a bending vibration, and the amplitude of α1M2 helix is the largest (Figure 5A). A recent single-molecule kinetic analysis on αM2 of nAChR suggested that most of the residues throughout the length of αM2 move relatively early in the gating reaction, but some at the mid-section move later [26]. This experimental result implies that the mid-section moves slower than the other part does, i.e., the αM2 might bend round the hinge during the gating process. This result gave an indirect support to the bending vibration of M2 helices, especially α1M2, as detected by our CMD simulation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China.

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 beta-sheet composed of beta9 and beta10 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.

Show MeSH
Related in: MedlinePlus