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 journalArticlepeer-review

31 Scopus citations


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
Issue number6
StatePublished - Mar 21 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics


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