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An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics.

ABSTRACT: Acetylcholine receptors mediate electrical signaling between nerve and muscle by opening and closing a transmembrane ion conductive pore. Molecular and Brownian dynamics simulations are used to shed light on the location and mechanism of the channel gate. Four separate 5 ns molecular dynamics simulations are carried out on the imaged structure of the channel, a hypothetical open structure with a slightly wider pore and a mutant structure in which a central ring of hydrophobic residues is replaced by polar groups. Water is found to partially evacuate the pore during molecular simulations of the imaged structure, whereas ions face a large energy barrier and do not conduct through the channel in Brownian dynamics simulations. The pore appears to be in a closed configuration despite containing an unobstructed pathway across the membrane as a series of hydrophobic residues in the center of the channel provide an unfavorable home to water and ions. When the channel is widened slightly, water floods into the channel and ions conduct at a rate comparable to the currents measured experimentally in open channels. The pore remains permeable to ions provided the extracellular end of the pore-lining helix is restrained near the putative open configuration to mimic the presence of the ligand binding domain. Replacing some of the hydrophobic residues with polar ones decreases the barrier for ion permeation but does not result in significant currents. The channel is posited to utilize an energy efficient gating mechanism in which only minor conformational changes of the hydrophobic region of the pore are required to create macroscopic changes in conductance.

SUBMITTER: Corry B

PROVIDER: S-EPMC1367105 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics.

Corry Ben B

Biophysical journal 20051111 3

Acetylcholine receptors mediate electrical signaling between nerve and muscle by opening and closing a transmembrane ion conductive pore. Molecular and Brownian dynamics simulations are used to shed light on the location and mechanism of the channel gate. Four separate 5 ns molecular dynamics simulations are carried out on the imaged structure of the channel, a hypothetical open structure with a slightly wider pore and a mutant structure in which a central ring of hydrophobic residues is replace ...[more]

PMID: 16284265

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Project description: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.

Dataset Information

An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics.

Publications

An energy-efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics.

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