Limits...
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.

Show MeSH

Related in: MedlinePlus

Pore Radius Profiles versus Position along the Pore AxisThree curves were produced on the basis of Cα atoms of M2 helices from the 20th ns snapshot as well as the structures resulting from the NMA on this snapshot.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211534&req=5

pcbi-0040019-g006: Pore Radius Profiles versus Position along the Pore AxisThree curves were produced on the basis of Cα atoms of M2 helices from the 20th ns snapshot as well as the structures resulting from the NMA on this snapshot.

Mentions: Recent NMA simulation studies based on a tentative model of the homomeric α7 neuronal nAChR [33,39] and the heteropentameric Torpedo nAChR [40] proposed a twist-to-open mechanism for nAChR dynamics. NMA was also applied to the nAChR in the present study to gain insight into the gating mechanism of this receptor. The snapshot at 20 ns on the CMD trajectory was extracted as the structure model for NMA, because the receptor reaches a more closed and stable state after such a lengthy CMD simulation (Figures 4, 5, and S1). The NMA results for the lowest-frequency modes are very similar to those of previous studies on the modeling structures of nAChR [33,39,40]; the detailed description for NMA is shown in the Figures S2–S4. In general, a global twisting motion occurs between the EC domain and the TM domain of nAChR. The first mode yielded symmetrical deformations of the entire nAChR structure. The five subunits of the EC domain and the corresponding M2 helices undergo concerted global rotations in opposite directions around the pore axis (see Figure S2). Other TM segments and MA helices undergo similar periodic rotations (Figure S3). Thus, the quintuple deformation of nAChR can be expressed in a twisting movement involving rotations of the EC and TM domains in opposite directions. Moreover, the global twisting motion of nAChR tends to increase the width of the entire pore, including the L- and V- rings, as indicated in Figure 6. These results are also in agreement with experimental [12,16,41–43] and recent theoretical studies [33,39,40].


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)

Pore Radius Profiles versus Position along the Pore AxisThree curves were produced on the basis of Cα atoms of M2 helices from the 20th ns snapshot as well as the structures resulting from the NMA on this snapshot.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-0040019-g006: Pore Radius Profiles versus Position along the Pore AxisThree curves were produced on the basis of Cα atoms of M2 helices from the 20th ns snapshot as well as the structures resulting from the NMA on this snapshot.
Mentions: Recent NMA simulation studies based on a tentative model of the homomeric α7 neuronal nAChR [33,39] and the heteropentameric Torpedo nAChR [40] proposed a twist-to-open mechanism for nAChR dynamics. NMA was also applied to the nAChR in the present study to gain insight into the gating mechanism of this receptor. The snapshot at 20 ns on the CMD trajectory was extracted as the structure model for NMA, because the receptor reaches a more closed and stable state after such a lengthy CMD simulation (Figures 4, 5, and S1). The NMA results for the lowest-frequency modes are very similar to those of previous studies on the modeling structures of nAChR [33,39,40]; the detailed description for NMA is shown in the Figures S2–S4. In general, a global twisting motion occurs between the EC domain and the TM domain of nAChR. The first mode yielded symmetrical deformations of the entire nAChR structure. The five subunits of the EC domain and the corresponding M2 helices undergo concerted global rotations in opposite directions around the pore axis (see Figure S2). Other TM segments and MA helices undergo similar periodic rotations (Figure S3). Thus, the quintuple deformation of nAChR can be expressed in a twisting movement involving rotations of the EC and TM domains in opposite directions. Moreover, the global twisting motion of nAChR tends to increase the width of the entire pore, including the L- and V- rings, as indicated in Figure 6. These results are also in agreement with experimental [12,16,41–43] and recent theoretical studies [33,39,40].

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