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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 ACh Binding Pockets Revealed by the SRMD Simulation(A–B) The time-dependence of RMSD values of the conserved residues consisting of type-I and type-II binding pockets, respectively.(C) The time-dependence of volumes of the binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.
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pcbi-0040019-g009: Dynamics of the ACh Binding Pockets Revealed by the SRMD Simulation(A–B) The time-dependence of RMSD values of the conserved residues consisting of type-I and type-II binding pockets, respectively.(C) The time-dependence of volumes of the binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.

Mentions: After having demonstrated the twisting motions of the whole receptor, the O ↔ C behavior of the pore channel (Figure 8C), and M2 bending based on the SRMD simulation results, we re-investigated changes in the ACh binding pockets. Because the clockwise motion is more plausible, we discuss the dynamics of the binding pockets based on the 1-ns SRMD simulation. As mentioned above, two ACh binding pockets, type-I and type-II, insert α1-γ and α2-δ interfaces, respectively. Conserved residues consisting of the two binding pockets were inspected during the 1-ns SRMD simulation. In agreement with the CMD simulation (Figure 2), the SRMD simulation also demonstrated the flexibility of the binding pockets. The SRMD profiles indicate that residues lining the binding pockets [44,45] experienced large movements (Figure 9). Similar to the CMD findings, SRMD results also indicate that C-loops are more flexible than A-loops and B-loops (Figure 9A and 9B). Unlike the results of CMD simulation (Figure 2A), the two binding pockets fluctuate along the SRMD trajectory, as shown in Figure 9C.


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 ACh Binding Pockets Revealed by the SRMD Simulation(A–B) The time-dependence of RMSD values of the conserved residues consisting of type-I and type-II binding pockets, respectively.(C) The time-dependence of volumes of the binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g009: Dynamics of the ACh Binding Pockets Revealed by the SRMD Simulation(A–B) The time-dependence of RMSD values of the conserved residues consisting of type-I and type-II binding pockets, respectively.(C) The time-dependence of volumes of the binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.
Mentions: After having demonstrated the twisting motions of the whole receptor, the O ↔ C behavior of the pore channel (Figure 8C), and M2 bending based on the SRMD simulation results, we re-investigated changes in the ACh binding pockets. Because the clockwise motion is more plausible, we discuss the dynamics of the binding pockets based on the 1-ns SRMD simulation. As mentioned above, two ACh binding pockets, type-I and type-II, insert α1-γ and α2-δ interfaces, respectively. Conserved residues consisting of the two binding pockets were inspected during the 1-ns SRMD simulation. In agreement with the CMD simulation (Figure 2), the SRMD simulation also demonstrated the flexibility of the binding pockets. The SRMD profiles indicate that residues lining the binding pockets [44,45] experienced large movements (Figure 9). Similar to the CMD findings, SRMD results also indicate that C-loops are more flexible than A-loops and B-loops (Figure 9A and 9B). Unlike the results of CMD simulation (Figure 2A), the two binding pockets fluctuate along the SRMD trajectory, as shown in Figure 9C.

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