dorsal/arxiv
View SchemaA Hydrophobic Gate in an Ion Channel: The Closed State of the Nicotinic Acetylcholine Receptor
| Authors | Oliver Beckstein, Mark S. P. Sansom |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0509018 |
| URL | https://arxiv.org/abs/q-bio/0509018 |
| DOI | 10.1088/1478-3975/3/2/007 |
| Journal | Physical Biology, 3(2):147-159, 2006 |
Abstract
The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the `Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic neurotransmission, and whose other members include receptors for glycine, gamma-aminobutyric acid, and serotonin. Cryo-electron microscopy has yielded a three dimensional structure of the nAChR in its closed state. However, the exact nature and location of the channel gate remains uncertain. Although the transmembrane pore is constricted close to its center, it is not completely occluded. Rather, the pore has a central hydrophobic zone of radius about 3 A. Model calculations suggest that such a constriction may form a hydrophobic gate, preventing movement of ions through a channel. We present a detailed and quantitative simulation study of the hydrophobic gating model of the nicotinic receptor, in order to fully evaluate this hypothesis. We demonstrate that the hydrophobic constriction of the nAChR pore indeed forms a closed gate. Potential of mean force (PMF) calculations reveal that the constriction presents a barrier of height ca. 10 kT to the permeation of sodium ions, placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 A radius hydrophobic pore can form a functional barrier to the permeation of a 1 A radius Na+ ion. Using a united atom force field for the protein instead of an all atom one retains the qualitative features but results in differing conductances, showing that the PMF is sensitive to the detailed molecular interactions.
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"abstract": "The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the\n`Cys-loop\u0027 superfamily of ligand-gated ion channels which mediate synaptic\nneurotransmission, and whose other members include receptors for glycine,\ngamma-aminobutyric acid, and serotonin. Cryo-electron microscopy has yielded a\nthree dimensional structure of the nAChR in its closed state. However, the\nexact nature and location of the channel gate remains uncertain. Although the\ntransmembrane pore is constricted close to its center, it is not completely\noccluded. Rather, the pore has a central hydrophobic zone of radius about 3 A.\nModel calculations suggest that such a constriction may form a hydrophobic\ngate, preventing movement of ions through a channel. We present a detailed and\nquantitative simulation study of the hydrophobic gating model of the nicotinic\nreceptor, in order to fully evaluate this hypothesis. We demonstrate that the\nhydrophobic constriction of the nAChR pore indeed forms a closed gate.\nPotential of mean force (PMF) calculations reveal that the constriction\npresents a barrier of height ca. 10 kT to the permeation of sodium ions,\nplacing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 A\nradius hydrophobic pore can form a functional barrier to the permeation of a 1\nA radius Na+ ion. Using a united atom force field for the protein instead of an\nall atom one retains the qualitative features but results in differing\nconductances, showing that the PMF is sensitive to the detailed molecular\ninteractions.",
"arxiv_id": "q-bio/0509018",
"authors": [
"Oliver Beckstein",
"Mark S. P. Sansom"
],
"categories": [
"q-bio.BM",
"q-bio.SC"
],
"doi": "10.1088/1478-3975/3/2/007",
"journal_ref": "Physical Biology, 3(2):147-159, 2006",
"title": "A Hydrophobic Gate in an Ion Channel: The Closed State of the Nicotinic Acetylcholine Receptor",
"url": "https://arxiv.org/abs/q-bio/0509018"
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