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Structure and functional dynamics characterization of the ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domain by combining molecular dynamics with excited normal modes

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Abstract

The human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infection in children and elderly people worldwide. Its genome encodes 11 proteins including SH protein, whose functions are not well known. Studies show that SH protein increases RSV virulence degree and permeability to small compounds, suggesting it is involved in the formation of ion channels. The knowledge of SH structure and function is fundamental for a better understanding of its infection mechanism. The aim of this study was to model, characterize, and analyze the structural behavior of SH protein in the phospholipids bilayer environment. Molecular modeling of SH pentameric structure was performed, followed by traditional molecular dynamics (MD) simulations of the protein immersed in the lipid bilayer. Molecular dynamics with excited normal modes (MDeNM) was applied in the resulting system in order to investigate long time scale pore dynamics. MD simulations support that SH protein is stable in its pentameric form. Simulations also showed the presence of water molecules within the bilayer by density distribution, thus confirming that SH protein is a viroporin. This water transport was also observed in MDeNM studies with histidine residues of five chains (His22 and His51), playing a key role in pore permeability. The combination of traditional MD and MDeNM was a very efficient protocol to investigate functional conformational changes of transmembrane proteins that act as molecular channels. This protocol can support future investigations of drug candidates by acting on SH protein to inhibit viral infection.

The ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domainᅟ

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References

  1. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352:1749–1759. doi:10.1056/NEJMoa043951

    Article  CAS  Google Scholar 

  2. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ et al. (2010) Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375:1545–1555. doi:10.1016/S0140-6736(10)60206-1

    Article  Google Scholar 

  3. Boyce TG, Mellen BG, Mitchel EF, Wright PF, Griffin MR (2000) Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr 137:865–870. doi:10.1067/mpd.2000.110531

    Article  CAS  Google Scholar 

  4. Collins PL, Hill MG, Cristina J, Grosfeld H (1996) Transcription elongation factor of respiratory syncytial virus, a nonsegmented negative-strand RNA virus. Proc Natl Acad Sci 93:81–85

    Article  CAS  Google Scholar 

  5. Kochva U, Leonov H, Arkin IT (2003) Modeling the structure of the respiratory syncytial virus small hydrophobic protein by silent-mutation analysis of global searching molecular dynamics. Protein Sci Publ Protein Soc 12:2668–2674

    Article  CAS  Google Scholar 

  6. Collins PL, Olmsted RA, Johnson PR (1990) The small hydrophobic protein of human respiratory syncytial virus: comparison between antigenic subgroups A and B. J Gen Virol 71(Pt 7):1571–1576

    Article  CAS  Google Scholar 

  7. Olmsted RA, Collins PL (1989) The 1A protein of respiratory syncytial virus is an integral membrane protein present as multiple, structurally distinct species. J Virol 63:2019–2029

    CAS  Google Scholar 

  8. Collins PL, Mottet G (1993) Membrane orientation and oligomerization of the small hydrophobic protein of human respiratory syncytial virus. J Gen Virol 74(Pt 7):1445–1450

    Article  CAS  Google Scholar 

  9. Jin H, Zhou H, Cheng X, Tang R, Munoz M, Nguyen N (2000) Recombinant respiratory syncytial viruses with deletions in the NS1, NS2, SH, and M2-2 genes are attenuated in vitro and in vivo. Virology 273:210–218. doi:10.1006/viro.2000.0393

    Article  CAS  Google Scholar 

  10. Whitehead SS, Bukreyev A, Teng MN, Firestone CY, Claire MS, Elkins WR et al. (1999) Recombinant respiratory syncytial virus bearing a deletion of either the NS2 or SH gene is attenuated in chimpanzees. J Virol 73:3438–3442

    CAS  Google Scholar 

  11. Heminway BR, Yu Y, Tanaka Y, Perrine KG, Gustafson E, Bernstein JM et al. (1994) Analysis of respiratory syncytial virus F, G, and SH proteins in cell fusion. Virology 200:801–805. doi:10.1006/viro.1994.1245

    Article  CAS  Google Scholar 

  12. Techaarpornkul S, Barretto N, Peeples ME (2001) Functional analysis of recombinant respiratory syncytial virus deletion mutants lacking the small hydrophobic and/or attachment glycoprotein gene. J Virol 75:6825–6834. doi:10.1128/JVI.75.15.6825-6834.2001

    Article  CAS  Google Scholar 

  13. Fuentes S, Tran KC, Luthra P, Teng MN, He B (2007) Function of the respiratory syncytial virus small hydrophobic protein. J Virol 81:8361–8366. doi:10.1128/JVI.02717-06

    Article  CAS  Google Scholar 

  14. He B, Lin GY, Durbin JE, Durbin RK, Lamb RA (2001) The SH integral membrane protein of the paramyxovirus simian virus 5 is required to block apoptosis in MDBK cells. J Virol 75:4068–4079. doi:10.1128/JVI.75.9.4068-4079.2001

    Article  CAS  Google Scholar 

  15. Gan S-W, Tan E, Lin X, Yu D, Wang J, Tan GM-Y et al. (2012) The small hydrophobic protein of the human respiratory syncytial virus forms pentameric ion channels. J Biol Chem 287:24671–24689. doi:10.1074/jbc.M111.332791

    Article  CAS  Google Scholar 

  16. Ramjeesingh M, Huan LJ, Garami E, Bear CE (1999) Novel method for evaluation of the oligomeric structure of membrane proteins. Biochem J 342:119–123

    Article  CAS  Google Scholar 

  17. Gan SW, Ng L, Lin X, Gong X, Torres J (2008) Structure and ion channel activity of the human respiratory syncytial virus (hRSV) small hydrophobic protein transmembrane domain. Protein Sci Publ Protein Soc 17:813–820. doi:10.1110/ps.073366208

    Article  CAS  Google Scholar 

  18. Perez M, Garcıa-Barreno B, Melero JA, Carrasco L, Guinea R (1997) Membrane permeability changes induced in escherichia coliby the sh protein of human respiratory syncytial virus. Virology 235:342–351. doi:10.1006/viro.1997.8696

    Article  CAS  Google Scholar 

  19. Gonzalez ME, Carrasco L (2003) Viroporins. FEBS Lett 552:28–34

    Article  CAS  Google Scholar 

  20. Rost B, Yachdav G, Liu J (2004) The PredictProtein server. Nucleic Acids Res 32:W321–W326. doi:10.1093/nar/gkh377

    Article  CAS  Google Scholar 

  21. Buchan DWA, Minneci F, Nugent TCO, Bryson K, Jones DT (2013) Scalable web services for the PSIPRED protein analysis workbench. Nucleic Acids Res 41:W349–W357. doi:10.1093/nar/gkt381

    Article  Google Scholar 

  22. Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinf 9:40. doi:10.1186/1471-2105-9-40

    Article  Google Scholar 

  23. Berendsen HJC, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56. doi:10.1016/0010-4655(95)00042-E

    Article  CAS  Google Scholar 

  24. Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R et al. (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics doi:10.1093/bioinformatics/btt055.

  25. Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J Comput Chem 25:1656–1676. doi:10.1002/jcc.20090

    Article  CAS  Google Scholar 

  26. Berger O, Edholm O, Jähnig F (1997) Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys J 72:2002–2013. doi:10.1016/S0006-3495(97)78845-3

    Article  CAS  Google Scholar 

  27. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) Interaction models for water in relation to protein hydration. In: Pullman B (ed) Intermolecular forces. Springer, Netherlands, pp 331–342

    Chapter  Google Scholar 

  28. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101. doi:10.1063/1.2408420

    Article  Google Scholar 

  29. Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690. doi:10.1063/1.448118

    Article  CAS  Google Scholar 

  30. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593. doi:10.1063/1.470117

    Article  CAS  Google Scholar 

  31. Nieva JL, Madan V, Carrasco L (2012) Viroporins: structure and biological functions. Nat Rev Microbiol 10:563–574. doi:10.1038/nrmicro2820

    Article  CAS  Google Scholar 

  32. Murzyn K, Róg T, Pasenkiewicz-Gierula M (2005) Phosphatidylethanolamine-phosphatidylglycerol bilayer as a model of the inner bacterial membrane. Biophys J 88:1091–1103. doi:10.1529/biophysj.104.048835

    Article  CAS  Google Scholar 

  33. Costa MGS, Batista PR, Bisch PM, Perahia D (2015) Exploring free energy landscapes of large conformational changes: molecular dynamics with excited normal modes. J Chem Theory Comput. doi:10.1021/acs.jctc.5b00003

    Google Scholar 

  34. Floquet N, Durand P, Maigret B, Badet B, Badet-Denisot M-A, Perahia D (2009) Collective motions in glucosamine-6-phosphate synthase: influence of ligand binding and role in ammonia channelling and opening of the fructose-6-phosphate binding site. J Mol Biol 385:653–664. doi:10.1016/j.jmb.2008.10.032

    Article  CAS  Google Scholar 

  35. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:187–217. doi:10.1002/jcc.540040211

    Article  CAS  Google Scholar 

  36. Li Y, To J, Verdià-Baguena C, Dossena S, Surya W, Huang M et al. (2014) Inhibition of the human respiratory syncytial virus small hydrophobic protein and structural variations in a Bicelle environment. J Virol 88:11899–11914. doi:10.1128/JVI.00839-14

    Article  Google Scholar 

  37. Wan S, Torres J (2011) Structural and functional aspects of the small hydrophobic (SH) protein in the human respiratory syncytial virus. In: Resch B (ed) Hum Respir Syncytial Virus Infect. InTech, doi:10.5772/28747

  38. Tamm LK, Tatulian SA (1997) Infrared spectroscopy of proteins and peptides in lipid bilayers. Q Rev Biophys 30:365–429

    Article  CAS  Google Scholar 

  39. Lin Y, Bright AC, Rothermel TA, He B (2003) Induction of apoptosis by paramyxovirus simian virus 5 lacking a small hydrophobic gene. J Virol 77:3371–3383. doi:10.1128/JVI.77.6.3371-3383.2003

    Article  CAS  Google Scholar 

  40. Jourd’heuil D, Aspinall A, Reynolds JD, Meddings JB (1996) Membrane fluidity increases during apoptosis of sheep ileal Peyer’s patch B cells. Can J Physiol Pharmacol 74:706–711

    Article  Google Scholar 

  41. Fujimoto K, Iwasaki C, Kawaguchi H, Yasugi E, Oshima M (1999) Cell membrane dynamics and the induction of apoptosis by lipid compounds. FEBS Lett 446:113–116. doi:10.1016/S0014-5793(99)00204-5

    Article  CAS  Google Scholar 

  42. Wilson RL, Fuentes SM, Wang P, Taddeo EC, Klatt A, Henderson AJ et al. (2006) Function of small hydrophobic proteins of paramyxovirus. J Virol 80:1700–1709. doi:10.1128/JVI.80.4.1700-1709.2006

    Article  CAS  Google Scholar 

  43. Triantafilou K, Kar S, Vakakis E, Kotecha S, Triantafilou M (2013) Human respiratory syncytial virus viroporin SH: a viral recognition pathway used by the host to signal inflammasome activation. Thorax 68:66–75. doi:10.1136/thoraxjnl-2012-202182

    Article  Google Scholar 

  44. Chen I-Y, Ichinohe T (2015) Response of host inflammasomes to viral infection. Trends Microbiol 23:55–63. doi:10.1016/j.tim.2014.09.007

    Article  CAS  Google Scholar 

  45. Daura X, Gademann K, Jaun B, Seebach D, van Gunsteren WF, Mark AE (1999) Peptide folding: when simulation meets experiment. Angew Chem Int Ed 38:236–240. doi:10.1002/(SICI)1521-3773(19990115)38:1/2<236::AID-ANIE236>3.0.CO;2-M

    Article  CAS  Google Scholar 

  46. Li Y, Jain N, Limpanawat S, To J, Quistgaard EM, Nordlund P et al. (2015) Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein. Virology 482:105–110. doi:10.1016/j.virol.2015.03.034

    Article  CAS  Google Scholar 

  47. Ambroggio EE, Separovic F, Bowie JH, Fidelio GD, Bagatolli LA (2005) Direct visualization of membrane leakage induced by the antibiotic peptides: maculatin, citropin, and aurein. Biophys J 89:1874–1881. doi:10.1529/biophysj.105.066589

    Article  CAS  Google Scholar 

  48. Lang F, Föller M, Lang KS, Lang PA, Ritter M, Gulbins E et al. (2005) Ion channels in cell proliferation and apoptotic cell death. J Membr Biol 205:147–157. doi:10.1007/s00232-005-0780-5

    Article  CAS  Google Scholar 

  49. Szabò I, Adams C, Gulbins E (2004) Ion channels and membrane rafts in apoptosis. Pflügers Arch Eur J Physiol 448:304–312

    Article  Google Scholar 

  50. Kochva U, Leonov H, Arkin IT (2003) Modeling the structure of the respiratory syncytial virus small hydrophobic protein by silent-mutation analysis of global searching molecular dynamics. Protein Sci 12:2668–2674. doi:10.1110/ps.03151103

    Article  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank the Brazilian Agencies FAPEMIG, CAPES, and CNPq for the financial support and the facilities GridUNESP, CENAPAD-SP, and V.B.P. Leite’s cluster (FAPESP grant 2011/17658-3) for the computational resources. ASA was supported by FAPESP grant 2010/18169-3.

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Authors and Affiliations

  1. Laboratório Multiusuário de Inovação Biomolecular, Departamento de Física, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista “Júlio de Mesquita Filho”, São José do Rio Preto, SP, Brazil

    Gabriela C. Araujo, Alexandre S. Araujo & Fatima P. Souza

  2. Laboratório de Biologia Computacional e Bioinformática, Universidade Federal do ABC, Santo André, SP, Brazil

    Ricardo H. T. Silva & Luis P. B. Scott

  3. Laboratório de Física Teórica, Departamento de Física, Instituto de Ciências Exatas, Naturais e Educação, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil

    Ronaldo Junio de Oliveira

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  1. Gabriela C. Araujo
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  3. Luis P. B. Scott
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Correspondence to Fatima P. Souza.

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Araujo, G.C., Silva, R.H.T., Scott, L.P.B. et al. Structure and functional dynamics characterization of the ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domain by combining molecular dynamics with excited normal modes. J Mol Model 22, 286 (2016). https://doi.org/10.1007/s00894-016-3150-6

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