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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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Related in: MedlinePlus

Schematic Representation of the Simulation System Constructed on the Basis of the Cryo-EM Structure of nAChR at 4 Å ResolutionnAChR is embedded in a DPPC lipid bilayer (green) and water molecules (red). Only three subunits (color-coded in red, blue, and yellow) are displayed for clarity. The M2 helices are rendered with electrostatic potential surface to highlight the pore shape.
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pcbi-0040019-g001: Schematic Representation of the Simulation System Constructed on the Basis of the Cryo-EM Structure of nAChR at 4 Å ResolutionnAChR is embedded in a DPPC lipid bilayer (green) and water molecules (red). Only three subunits (color-coded in red, blue, and yellow) are displayed for clarity. The M2 helices are rendered with electrostatic potential surface to highlight the pore shape.

Mentions: The nAChR was embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer [18,27], the nAChR/DPPC complex was solvated using a bath of the simple point charge (SPC) water molecules [28], and the whole system was neutralized by adding numbers of Na+ and Cl− ions, giving rise to a final simulation system containing more than 250,000 atoms. The schematic representation of the simulation system is shown in Figure 1. Firstly, the system was equilibrated by running a short (950 ps) MD simulation. The root mean square deviation (RMSD) between the final equilibrated structure of nAChR and the original structure is 1.02 Å. A 30-ns CMD simulation was subsequently performed and the MD trajectory was used to analyze the conformational dynamics of the receptor.


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)

Schematic Representation of the Simulation System Constructed on the Basis of the Cryo-EM Structure of nAChR at 4 Å ResolutionnAChR is embedded in a DPPC lipid bilayer (green) and water molecules (red). Only three subunits (color-coded in red, blue, and yellow) are displayed for clarity. The M2 helices are rendered with electrostatic potential surface to highlight the pore shape.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g001: Schematic Representation of the Simulation System Constructed on the Basis of the Cryo-EM Structure of nAChR at 4 Å ResolutionnAChR is embedded in a DPPC lipid bilayer (green) and water molecules (red). Only three subunits (color-coded in red, blue, and yellow) are displayed for clarity. The M2 helices are rendered with electrostatic potential surface to highlight the pore shape.
Mentions: The nAChR was embedded in a dipalmitoylphosphatidylcholine (DPPC) bilayer [18,27], the nAChR/DPPC complex was solvated using a bath of the simple point charge (SPC) water molecules [28], and the whole system was neutralized by adding numbers of Na+ and Cl− ions, giving rise to a final simulation system containing more than 250,000 atoms. The schematic representation of the simulation system is shown in Figure 1. Firstly, the system was equilibrated by running a short (950 ps) MD simulation. The root mean square deviation (RMSD) between the final equilibrated structure of nAChR and the original structure is 1.02 Å. A 30-ns CMD simulation was subsequently performed and the MD trajectory was used to analyze the conformational dynamics of the receptor.

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