Molecular dynamics simulations of the Cx26 hemichannel

Insights into voltage-dependent loop-gating

Taekyung Kwon, Benoît Roux, Sunhwan Jo, Jeffery B. Klauda, Andrew L. Harris, Thaddeus A. Bargiello

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Loop-gating is one of two voltage-dependent mechanisms that regulate the open probability of connexin channels. The loop-gate permeability barrier is formed by a segment of the first extracellular loop (E1) (the parahelix) and appears to be accompanied by straightening of the bend angle between E1 and the first transmembrane domain (TM1). Here, all-atom molecular dynamics simulations are used to identify and characterize interacting van der Waals and electrostatic networks that stabilize the parahelices and TM1/E1 bend angles of the open Cx26 hemichannel. Dynamic fluctuations in an electrostatic network in each subunit are directly linked to the stability of parahelix structure and TM1/E1 bend angle in adjacent subunits. The electrostatic network includes charged residues that are pore-lining and thus positioned to be voltage sensors. We propose that the transition to the closed state is initiated by voltage-driven disruption of the networks that stabilize the open-state parahelix configuration, allowing the parahelix to protrude into the channel pore to form the loop-gate barrier. Straightening of the TM1/E1 bend appears to be a consequence of the reorganization of the interacting networks that accompany the conformational change of the parahelix. The electrostatic network extends across subunit boundaries, suggesting a concerted gating mechanism.

Original languageEnglish (US)
Pages (from-to)1341-1351
Number of pages11
JournalBiophysical Journal
Volume102
Issue number6
DOIs
StatePublished - Mar 21 2012

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Molecular Dynamics Simulation
Static Electricity
Connexins
Permeability

ASJC Scopus subject areas

  • Biophysics

Cite this

Kwon, T., Roux, B., Jo, S., Klauda, J. B., Harris, A. L., & Bargiello, T. A. (2012). Molecular dynamics simulations of the Cx26 hemichannel: Insights into voltage-dependent loop-gating. Biophysical Journal, 102(6), 1341-1351. https://doi.org/10.1016/j.bpj.2012.02.009

Molecular dynamics simulations of the Cx26 hemichannel : Insights into voltage-dependent loop-gating. / Kwon, Taekyung; Roux, Benoît; Jo, Sunhwan; Klauda, Jeffery B.; Harris, Andrew L.; Bargiello, Thaddeus A.

In: Biophysical Journal, Vol. 102, No. 6, 21.03.2012, p. 1341-1351.

Research output: Contribution to journalArticle

Kwon, T, Roux, B, Jo, S, Klauda, JB, Harris, AL & Bargiello, TA 2012, 'Molecular dynamics simulations of the Cx26 hemichannel: Insights into voltage-dependent loop-gating', Biophysical Journal, vol. 102, no. 6, pp. 1341-1351. https://doi.org/10.1016/j.bpj.2012.02.009
Kwon, Taekyung ; Roux, Benoît ; Jo, Sunhwan ; Klauda, Jeffery B. ; Harris, Andrew L. ; Bargiello, Thaddeus A. / Molecular dynamics simulations of the Cx26 hemichannel : Insights into voltage-dependent loop-gating. In: Biophysical Journal. 2012 ; Vol. 102, No. 6. pp. 1341-1351.
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