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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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Collective Motions of the C-Loops, M1, and M2 Helices(A) The time-dependence of the volumes of ACh binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.(B) The motion tendencies of C-loops, M1, and M2 reflected by the superposition of subunit α1 at the beginning (green) and after 30 ns simulation (cyan). The picture is displayed parallel to the pore axis.(C–D) The anticlockwise motions of the M1 and M2 helices. The superpositions are based on the centers of mass of the five M1 and M2 helices, respectively, and the pictures are viewed from the synaptic cleft.
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pcbi-0040019-g002: Collective Motions of the C-Loops, M1, and M2 Helices(A) The time-dependence of the volumes of ACh binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.(B) The motion tendencies of C-loops, M1, and M2 reflected by the superposition of subunit α1 at the beginning (green) and after 30 ns simulation (cyan). The picture is displayed parallel to the pore axis.(C–D) The anticlockwise motions of the M1 and M2 helices. The superpositions are based on the centers of mass of the five M1 and M2 helices, respectively, and the pictures are viewed from the synaptic cleft.

Mentions: ACh binding is essential to the gating of nAChR, which induces a conformational change that opens the channel [16,29]. We therefore first of all investigated the dynamics of the ACh binding pockets. For the subtype of nAChR we studied, there are two binding pockets located at the interfaces between α1 and γ subunits (type-I) and between α2 and δ subunits (type-II), respectively [12,30]. These two binding pockets were monitored throughout the 30-ns CMD simulation by using the SURFNET program [31]. As indicated in Figure 2A, both type-I and type-II ACh binding pockets shrunk significantly during the 30-ns CMD simulation. The α-subunit C-loops act as lids of the binding pockets. The flexibility of C-loops was observed experimentally [32] and theoretically [20,33]. Our CMD simulation indicates that the C-loop of each α-subunit moves inward toward the center of the molecule (Figure 2B); this motion is the major cause of shrinkage of the ACh binding pocket. Concomitantly, the inward motion of C-loops drives the outer β-sheet (made up of strands β9 and β10) inward and upward, in particular the bottom part, as shown in Figure 2B. This motion further stimulates the movement of M1 (Figure 2B). Taking the movements of the five subunits together, it can be seen that the five M1 helices perform an anticlockwise rotation around the pore axis, as viewed from the top of the receptor (Figure 2C). Since M2 connects directly with M1 through a loop, the rotation of M1 should induce M2 to rotate around the pore axis in the same direction. Indeed, viewed from the synaptic cleft, the 5-fold M2 helices rotate in an anticlockwise manner around the pore axis, as shown in Figure 2D. Accordingly, the 30-ns CMD simulation detected a clear correlation between the motions of the ACh binding pockets, C-loops, and the M1 and M2 helices.


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)

Collective Motions of the C-Loops, M1, and M2 Helices(A) The time-dependence of the volumes of ACh binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.(B) The motion tendencies of C-loops, M1, and M2 reflected by the superposition of subunit α1 at the beginning (green) and after 30 ns simulation (cyan). The picture is displayed parallel to the pore axis.(C–D) The anticlockwise motions of the M1 and M2 helices. The superpositions are based on the centers of mass of the five M1 and M2 helices, respectively, and the pictures are viewed from the synaptic cleft.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g002: Collective Motions of the C-Loops, M1, and M2 Helices(A) The time-dependence of the volumes of ACh binding pockets. Black and red curves represent type-I (α1-γ) and type-II (α2-δ) pockets, respectively.(B) The motion tendencies of C-loops, M1, and M2 reflected by the superposition of subunit α1 at the beginning (green) and after 30 ns simulation (cyan). The picture is displayed parallel to the pore axis.(C–D) The anticlockwise motions of the M1 and M2 helices. The superpositions are based on the centers of mass of the five M1 and M2 helices, respectively, and the pictures are viewed from the synaptic cleft.
Mentions: ACh binding is essential to the gating of nAChR, which induces a conformational change that opens the channel [16,29]. We therefore first of all investigated the dynamics of the ACh binding pockets. For the subtype of nAChR we studied, there are two binding pockets located at the interfaces between α1 and γ subunits (type-I) and between α2 and δ subunits (type-II), respectively [12,30]. These two binding pockets were monitored throughout the 30-ns CMD simulation by using the SURFNET program [31]. As indicated in Figure 2A, both type-I and type-II ACh binding pockets shrunk significantly during the 30-ns CMD simulation. The α-subunit C-loops act as lids of the binding pockets. The flexibility of C-loops was observed experimentally [32] and theoretically [20,33]. Our CMD simulation indicates that the C-loop of each α-subunit moves inward toward the center of the molecule (Figure 2B); this motion is the major cause of shrinkage of the ACh binding pocket. Concomitantly, the inward motion of C-loops drives the outer β-sheet (made up of strands β9 and β10) inward and upward, in particular the bottom part, as shown in Figure 2B. This motion further stimulates the movement of M1 (Figure 2B). Taking the movements of the five subunits together, it can be seen that the five M1 helices perform an anticlockwise rotation around the pore axis, as viewed from the top of the receptor (Figure 2C). Since M2 connects directly with M1 through a loop, the rotation of M1 should induce M2 to rotate around the pore axis in the same direction. Indeed, viewed from the synaptic cleft, the 5-fold M2 helices rotate in an anticlockwise manner around the pore axis, as shown in Figure 2D. Accordingly, the 30-ns CMD simulation detected a clear correlation between the motions of the ACh binding pockets, C-loops, and the M1 and M2 helices.

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