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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

Changes of the Pore Channel(A) Pore radius profiles versus position along the pore axis. Curves represent the average radii changes over different time intervals for the all-atoms (top) and Cα atoms (bottom) of the five M2 helices.(B) The volume change of the pore channel reflected by the water molecules embedded within the channel.
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pcbi-0040019-g004: Changes of the Pore Channel(A) Pore radius profiles versus position along the pore axis. Curves represent the average radii changes over different time intervals for the all-atoms (top) and Cα atoms (bottom) of the five M2 helices.(B) The volume change of the pore channel reflected by the water molecules embedded within the channel.

Mentions: M2 helices line the innermost wall of the channel and thus their motions and conformational changes are directly associated with the gating of the receptor. Changes in channel radii along the pore were monitored during the 30-ns CMD trajectory using the HOLE program [36–38]. The results indicate that the channel undergoes a visible reduction, as reflected by the changes in the radius profiles (Figure 4A). Consistent with the conclusion from earlier, lower resolution cryo-EM structure of the nAChR [16], the extent of decreases in channel radii is most prominent in the conserved hydrophobic regions around the L251 and V255 rings (L- and V-rings). Furthermore, the radius change profiles indicate that the side-chains of inner residues of M2 helices move more deeply toward the pore axis than do the Cα atoms (Figure 4A). The shrinkage of the pore channel is also reflected by the change in the amount of water molecules inside the channel. As shown in Figure 4B, the number of intrachannel water molecules decreased from 181 to 134 after 30 ns simulation. Particularly remarkable was the narrowing of the middle segment of M2 helices around the L- and V-rings, turning into vacuo.


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)

Changes of the Pore Channel(A) Pore radius profiles versus position along the pore axis. Curves represent the average radii changes over different time intervals for the all-atoms (top) and Cα atoms (bottom) of the five M2 helices.(B) The volume change of the pore channel reflected by the water molecules embedded within the channel.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g004: Changes of the Pore Channel(A) Pore radius profiles versus position along the pore axis. Curves represent the average radii changes over different time intervals for the all-atoms (top) and Cα atoms (bottom) of the five M2 helices.(B) The volume change of the pore channel reflected by the water molecules embedded within the channel.
Mentions: M2 helices line the innermost wall of the channel and thus their motions and conformational changes are directly associated with the gating of the receptor. Changes in channel radii along the pore were monitored during the 30-ns CMD trajectory using the HOLE program [36–38]. The results indicate that the channel undergoes a visible reduction, as reflected by the changes in the radius profiles (Figure 4A). Consistent with the conclusion from earlier, lower resolution cryo-EM structure of the nAChR [16], the extent of decreases in channel radii is most prominent in the conserved hydrophobic regions around the L251 and V255 rings (L- and V-rings). Furthermore, the radius change profiles indicate that the side-chains of inner residues of M2 helices move more deeply toward the pore axis than do the Cα atoms (Figure 4A). The shrinkage of the pore channel is also reflected by the change in the amount of water molecules inside the channel. As shown in Figure 4B, the number of intrachannel water molecules decreased from 181 to 134 after 30 ns simulation. Particularly remarkable was the narrowing of the middle segment of M2 helices around the L- and V-rings, turning into vacuo.

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