title: Characterization of a novel water pocket inside the human Cx26 hemichannel structure.
abstract: Connexins (Cxs) are a family of vertebrate proteins constituents of gap junction channels (GJCs) that connect the cytoplasm of adjacent cells by the end-to-end docking of two Cx hemichannels. The intercellular transfer through GJCs occurs by passive diffusion allowing the exchange of water, ions, and small molecules. Despite the broad interest to understand, at the molecular level, the functional state of Cx-based channels, there are still many unanswered questions regarding structure-function relationships, perm-selectivity, and gating mechanisms. In particular, the ordering, structure, and dynamics of water inside Cx GJCs and hemichannels remains largely unexplored. In this work, we describe the identification and characterization of a believed novel water pocket-termed the IC pocket-located in-between the four transmembrane helices of each human Cx26 (hCx26) monomer at the intracellular (IC) side. Using molecular dynamics (MD) simulations to characterize hCx26 internal water structure and dynamics, six IC pockets were identified per hemichannel. A detailed characterization of the dynamics and ordering of water including conformational variability of residues forming the IC pockets, together with multiple sequence alignments, allowed us to propose a functional role for this cavity. An in vitro assessment of tracer uptake suggests that the IC pocket residue Arg-143 plays an essential role on the modulation of the hCx26 hemichannel permeability.
authors.affiliation: Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Raul
authors.initials: R
authors.lastname: Araya-Secchi
authors.affiliation: Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso. Electronic address: tomas@dlab.cl.
authors.forename: Tomas
authors.initials: T
authors.lastname: Perez-Acle
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York.
authors.forename: Seung-Gu
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York.
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.affiliation: Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Bernardin
authors.affiliation: Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Yerko
authors.initials: Y
authors.lastname: Escalona
authors.affiliation: Computational Biology Lab (DLab), Fundación Ciencia & Vida, Ñuñoa, Santiago; Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Jose-Antonio
authors.initials: JA
authors.lastname: Garate
authors.affiliation: Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Agustin D
authors.initials: AD
authors.lastname: Martínez
authors.affiliation: Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso.
authors.forename: Isaac E
authors.initials: IE
authors.lastname: García
authors.affiliation: Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Universidad de Valparaíso, Valparaíso; Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York. Electronic address: ruhongz@us.ibm.com.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000072259:Connexin 26; D017630:Connexins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D014867:Water; D000072259:Connexin 26
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