title: Computational Study of Binding of μ-Conotoxin GIIIA to Bacterial Sodium Channels NaVAb and NaVRh.
abstract: Structures of several voltage-gated sodium (NaV) channels from bacteria have been determined recently, but the same feat might not be achieved for the mammalian counterparts in the near future. Thus, at present, computational studies of the mammalian NaV channels have to be performed using homology models based on the bacterial crystal structures. A successful homology model for the mammalian NaV1.4 channel was recently constructed using the extensive mutation data for binding of μ-conotoxin GIIIA to NaV1.4, which was further validated through studies of binding of other μ-conotoxins and ion permeation. Understanding the similarities and differences between the bacterial and mammalian NaV channels is an important issue, and the NaV1.4-GIIIA system provides a good opportunity for such a comparison. To this end, we study the binding of GIIIA to the bacterial channels NaVAb and NaVRh. The complex structures are obtained using docking and molecular dynamics simulations, and the dissociation of GIIIA is studied through umbrella sampling simulations. The results are compared to those obtained from the NaV1.4-GIIIA system, and the differences in the binding modes arising from the changes in the selectivity filters are highlighted.
authors.affiliation: School of Physics, University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Dharmeshkumar
authors.initials: D
authors.lastname: Patel
authors.affiliation: School of Physics, University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Somayeh
authors.initials: S
authors.lastname: Mahdavi
authors.affiliation: School of Physics, University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: Serdar
authors.initials: S
authors.lastname: Kuyucak
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods*; D020916:Conotoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D020916:Conotoxins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D015222:Sodium Channels; C046101:conotoxin GIII