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Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics

The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivi...

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Autores principales: Kwon, Taekyung, Harris, Andrew L., Rossi, Angelo, Bargiello, Thaddeus A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206306/
https://www.ncbi.nlm.nih.gov/pubmed/22006989
http://dx.doi.org/10.1085/jgp.201110679
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author Kwon, Taekyung
Harris, Andrew L.
Rossi, Angelo
Bargiello, Thaddeus A.
author_facet Kwon, Taekyung
Harris, Andrew L.
Rossi, Angelo
Bargiello, Thaddeus A.
author_sort Kwon, Taekyung
collection PubMed
description The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion selectivity of Cx26 channels. Furthermore, the simulations and data suggest that experimentally observed heterogeneity in Cx26 I-V relations can be accounted for by variation in co- and posttranslational modifications.
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spelling pubmed-32063062012-05-01 Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics Kwon, Taekyung Harris, Andrew L. Rossi, Angelo Bargiello, Thaddeus A. J Gen Physiol Article The recently published crystal structure of the Cx26 gap junction channel provides a unique opportunity for elucidation of the structure of the conductive connexin pore and the molecular determinants of its ion permeation properties (conductance, current–voltage [I-V] relations, and charge selectivity). However, the crystal structure was incomplete, most notably lacking the coordinates of the N-terminal methionine residue, which resides within the pore, and also lacking two cytosolic domains. To allow computational studies for comparison with the known channel properties, we completed the structure. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) simulations of the completed and the published Cx26 hemichannel crystal structure indicate that the pore is too narrow to permit significant ion flux. The GCMC/BD simulations predict marked inward current rectification and almost perfect anion selectivity, both inconsistent with known channel properties. The completed structure was refined by all-atom molecular dynamics (MD) simulations (220 ns total) in an explicit solvent and POPC membrane system. These MD simulations produced an equilibrated structure with a larger minimal pore diameter, which decreased the height of the permeation barrier formed by the N terminus. GCMC/BD simulations of the MD-equilibrated structure yielded more appropriate single-channel conductance and less anion/cation selectivity. However, the simulations much more closely matched experimentally determined I-V relations when the charge effects of specific co- and posttranslational modifications of Cx26 previously identified by mass spectrometry were incorporated. We conclude that the average equilibrated structure obtained after MD simulations more closely represents the open Cx26 hemichannel structure than does the crystal structure, and that co- and posttranslational modifications of Cx26 hemichannels are likely to play an important physiological role by defining the conductance and ion selectivity of Cx26 channels. Furthermore, the simulations and data suggest that experimentally observed heterogeneity in Cx26 I-V relations can be accounted for by variation in co- and posttranslational modifications. The Rockefeller University Press 2011-11 /pmc/articles/PMC3206306/ /pubmed/22006989 http://dx.doi.org/10.1085/jgp.201110679 Text en © 2011 Kwon et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Kwon, Taekyung
Harris, Andrew L.
Rossi, Angelo
Bargiello, Thaddeus A.
Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title_full Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title_fullStr Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title_full_unstemmed Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title_short Molecular dynamics simulations of the Cx26 hemichannel: Evaluation of structural models with Brownian dynamics
title_sort molecular dynamics simulations of the cx26 hemichannel: evaluation of structural models with brownian dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206306/
https://www.ncbi.nlm.nih.gov/pubmed/22006989
http://dx.doi.org/10.1085/jgp.201110679
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