title: Genotype-specific differences in structural features of hepatitis C virus (HCV) p7 membrane protein.
abstract: The 63 amino acid polytopic membrane protein, p7, encoded by hepatitis C virus (HCV) is involved in the modulation of electrochemical gradients across membranes within infected cells. Structural information relating to p7 from multiple genotypes has been generated in silico (e.g. genotype (GT) 1a), as well as obtained from experiments in form of monomeric and hexameric structures (GTs 1b and 5a, respectively). However, sequence diversity and structural differences mean that comparison of their channel gating behaviour has not thus far been simulated. Here, a molecular model of the monomeric GT 1a protein is optimized and assembled into a hexameric bundle for comparison with both the 5a hexamer structure and another hexameric bundle generated using the GT 1b monomer structure. All bundles tend to turn into a compact structure during molecular dynamics (MD) simulations (Gromos96 (ffG45a3)) in hydrated lipid bilayers, as well as when simulated at 'low pH', which may trigger channel opening according to some functional studies. Both GT 1a and 1b channel models are gated via movement of the parallel aligned helices, yet the scenario for the GT 5a protein is more complex, with a short N-terminal helix being involved. However, all bundles display pulsatile dynamics identified by monitoring water dynamics within the pore.
authors.affiliation: Institute of Biophotonics, School of Biomedical Science and Engineering, Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, TW.
authors.forename: Monoj Mon
authors.initials: MM
authors.lastname: Kalita
authors.affiliation: Leeds Institute of Cancer & Pathology, Faculty of Medicine and Health, St James' University Hospital, University of Leeds, Beckett St., Leeds, West Yorkshire LS9 7TF, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Griffin
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Chou
authors.affiliation: Institute of Biophotonics, School of Biomedical Science and Engineering, Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, TW. Electronic address: wfischer@ym.edu.tw.
authors.forename: Wolfgang B
authors.initials: WB
authors.lastname: Fischer
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D003198:Computer Simulation; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010539:Permeability; D017434:Protein Structure, Tertiary; D011522:Protons; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics*; D014867:Water / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D000596:Amino Acids; D011522:Protons; D014764:Viral Proteins; D014867:Water; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins
keywords: Channel gating; Genotypes; Molecular dynamics simulation; NMR structure; Viral channel protein; p7 of HCV