title: Molecular dynamics simulations of the Cx26 hemichannel: insights into voltage-dependent loop-gating.
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.
authors.affiliation: Dominic P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Taekyung
authors.initials: T
authors.lastname: Kwon
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.forename: Sunhwan
authors.initials: S
authors.lastname: Jo
authors.forename: Jeffery B
authors.initials: JB
authors.lastname: Klauda
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
authors.forename: Thaddeus A
authors.initials: TA
authors.lastname: Bargiello
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism; D000072259:Connexin 26; D017630:Connexins / Q000737:chemistry* / Q000378:metabolism*; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D010539:Permeability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
chemical_list: D000596:Amino Acids; D017630:Connexins; D007473:Ion Channels; D021122:Protein Subunits; D000072259:Connexin 26