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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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The Time-Dependence of the Rotational Angles of the EC domain, M1–M4 and MA helices, with Respect to Their Starting Structures
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pcbi-0040019-g003: The Time-Dependence of the Rotational Angles of the EC domain, M1–M4 and MA helices, with Respect to Their Starting Structures

Mentions: Taking into account the rotating motions of M1 and M2 helices, we subsequently investigated the circumgyrations of the other components of nAChR by determining the rotation angles of the EC domain, TM, and intracellular MA helices. The rotation angle of each body as a whole (for instance the five M1 or M2 helices) was derived rigorously from the moment of inertia. Details of the method used to calculate the rotation angles are given in the Materials and Methods section. As indicated in Figure 3, both TM helices (M1–M4) and non-TM MA helices undergo global anticlockwise rotations with respect to the EC domain. The intracellular MA helices, exposed to the water milieu, experienced the most pronounced rotation of all nAChR helices, whereas the EC domain is the most static part of the whole receptor. The rotation of the M2 helices in the TM domain is more pronounced than that of other TM segments, which is in agreement with previous simulation result [34] and supports the viewpoint that the innermost M2 ring constitutes a distinct assembly within the TM region [35]. The second most pronounced rotation among TM segments corresponds to the M1 helices. The M3 and M4 helices rotate relatively slower in comparison with 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)

The Time-Dependence of the Rotational Angles of the EC domain, M1–M4 and MA helices, with Respect to Their Starting Structures
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g003: The Time-Dependence of the Rotational Angles of the EC domain, M1–M4 and MA helices, with Respect to Their Starting Structures
Mentions: Taking into account the rotating motions of M1 and M2 helices, we subsequently investigated the circumgyrations of the other components of nAChR by determining the rotation angles of the EC domain, TM, and intracellular MA helices. The rotation angle of each body as a whole (for instance the five M1 or M2 helices) was derived rigorously from the moment of inertia. Details of the method used to calculate the rotation angles are given in the Materials and Methods section. As indicated in Figure 3, both TM helices (M1–M4) and non-TM MA helices undergo global anticlockwise rotations with respect to the EC domain. The intracellular MA helices, exposed to the water milieu, experienced the most pronounced rotation of all nAChR helices, whereas the EC domain is the most static part of the whole receptor. The rotation of the M2 helices in the TM domain is more pronounced than that of other TM segments, which is in agreement with previous simulation result [34] and supports the viewpoint that the innermost M2 ring constitutes a distinct assembly within the TM region [35]. The second most pronounced rotation among TM segments corresponds to the M1 helices. The M3 and M4 helices rotate relatively slower in comparison with 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