Prediction of a neutralizing epitope of a H5N1 virus hemagglutinin complexed with an antibody variable fragment using molecular dynamics simulation

Cenmidtal C. Mulyanto, Rosari Saleh

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Departemen Fisika, Fakultas MIPA, Kampus Universitas Indonesia, Depok, Indonesia 16424;.

DOI: 10.4236/jbpc.2011.23031                

Abstract

In this present study, we predicted the neutralizing epitope of a modeled H5N1 hemagglutinin 1046T when interacted with a modeled monoclonal antibody variable fragment 8H5Fv using molecular dynamics simulation. Following the production run of the molecular dynamics simulation, we observed the average change of solvent accessible surface of the antigen alongside the formation of hydrogen bonds between the two structures during the simulation. Based on the acquired data, we predicted the neutralizing epitope of the 1046T antigen to be consisted of residues Asp 84, Glu85, Phe86, Ile87, Asn88, Val89, Pro90, Ile132, Ser136, Val147, Pro152, Tyr153, Leu154, Arg161, and Tyr268. By calculating the RMSD of the Cα backbone chain of the complex during the simulation we found the structure to be generally stable suggesting a well maintained steric hindrance, while RMSD calculation of the predicted neutralizing epitope backbone suggests the stability of the neutralizing epitope itself.

Keywords

Molecular Dynamics Simulation; Neutralizing Epitope; Antibody; H5N1 Hemagglutinin; Molecular Docking

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 (2005) Avian influenza A (H5N1) infection in humans. The New England Journal of Medicine Volume, 353, 1374-1385. doi:10.1056/NEJMra052211
[2]	World Health Organzation (2009) Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. http://www.who.int
[3]	De Jong, M.D. and Hien, T.T. (2006) Avian influenza A (H5N1). Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.
[4]	Kamps, B.S., Hoffman, C. and Preiser, W. (2006) Influenza Report 2006, Flying Publisher, Paris. http://www.infleunzareport.com
[5]	Swayne, D.E., (2008) Avian influenza. Blackwell Publishing, Ames.
[6]	Lim, A., Wong, S., Chan, A., Chan, C., Ooi, E. and Hanson, B. (2008) Epitope characterization of the protective monoclonal antibody VN04-2 shows broadly neutralizing against highly pathogenic H5N1. Virology Journal, 5, 80. doi:10.1186/1743-422X-5-80
[7]	Philpot M., Easterday B.C. and Hinshaw V.S. (1989) Neutralizing epitopes of the H5 hemagglutinin from a virulent avian influenza virus and their relationship to pathogenicity. The Journal of Virology, 63, 3453-3458.
[8]	Yan, Y.Q., Li, S., Yang, C.Y., Luo, W.X., Wang, M.Q., Chen, Y.X., Luo, H.F., Wu, T.Z. and Xia, N.S. (2008) Prediction of a common neutralizing epitope of H5N1 avian influenza virus by in silico molecular docking. Chinese Science Bulletin, 53, 868-877. doi:10.1007/s11434-008-0161-4
[9]	Okuno,Y., Isegawa, Y., Sasao, F. and Ueda, dan S. (1999) A common neutralizing epitope conserved between the haemagglutinins influenza virus a H1 and H2 strains. Journal of Virology, 67, 2552-2558.
[10]	Yen, H.L. and Peiris, J.S.M. (2009) Mapping antibody epitopes of the avian H5N1 influenza virus. PloS Medicine, 6, e1000064. doi.org/10.1371/journal.pmed.1000064
[11]	Jensen, F. (2007) Introduction to computational chemistry. 2nd Edition, John Wiley & Sons, Ltd., Chichester.
[12]	Mulholland, A.J. (2008) Introduction: Biomolecular simulation. Journal of the Royal Society Interface, 5, S169-S172. doi:10.1098/rsif.2008.0385.focus
[13]	Leach, A. (2001) Molecular modeling: Principles and application. Prentice Hall, Upper Saddle River.
[14]	Morea, V., Lesk, A.M. and Tramontano, A. (2009) Antibody modeling: Implications for engineering and design. Methods, 20, 267-279. doi:10.1006/meth.1999.0921
[15]	Chen, R. and Weng, Z. (2003) A novel shape complimentarity scoring function for Protein—Protein docking. Poteins, 5, 397-408.
[16]	Chen, R., Tong, W., Mintseris, J., Li, L. and Weng, Z. (2003) ZDOCK predictions for the CAPRI challenge. PROTEINS: Structure, Function, and Genetics, 52, 68-73. doi:10.1002/prot.10388
[17]	Wiehe, K., Pierce, B., Mintseris, J., Tong, W., Anderson, R., Chen, R. and Weng, Z. (2005) ZDOCK and RDOCK performance in CAPRI rounds 3, 4, and 5. Proteins, 60, 207-213. doi:10.1002/prot.20559
[18]	Connolly, M.L. (1983) Solvent accessible surfaces of proteins and nucleic acids. Science, 221,709-713. doi:10.1126/science.6879170
[19]	Durham, E., Dorr B., Woetzel N., Staritzbichler, and Meiler, J. (2009) Solvent accessible surface area approximations for rapid and accurate protein structure prediction. Journal of Molecular Modeling, 15, 1093- 1108. doi:10.1007/s00894-009-0454-9
[20]	Rose, G.D. (1993) Hydrogen bonding, hydrophobicity, packing, and protein folding. Annual Review of Bioph- ysics and Biomolecular Structure, 22, 381-415. doi:10.1146/annurev.bb.22.060193.002121
[21]	Wong, S., Bernacki, K. and Jacobson, M. (2005) Competition between intramolecular hydrogen bonds and salvation in phosphorylated peptides: Simulations with explicit and implicit solvent. The Journal of Physical Chemistry B, 109, 5249-5258. doi:10.1021/jp046333q
[22]	Feig, M., Onufriev, A., Lee, M.S., Im, W., Case, D.A. and Brooks, C.L. (2004) Performance comparison of gener- alized born and poisson methods in the calculation of electrostatic solvation energies for protein structures. Journal of Computational Chemistry, 25, 265-284. do:10.1002/jcc.10378
[23]	Arnold, K., Bordoli, L., Kopp, J. and Schwede, T. (2006) The SWISS-MODEL workspace: A web-based environ- ment for protein structure homology modelling. Bioinformatics, 22, 195-201. doi:10.1093/bioinformatics/bti770
[24]	Peitsch, M.C. (1995) Protein modeling by E-mail. Bio/Technology, 13, 658-660. doi:10.1038/nbt0795-658
[25]	Sircar, A., Kim, E. and Gray, J.J. (2009) Rosetta antibody: Antibody variable region homology modeling server. Nucleic Acids Research, 37, W474-W479.
[26]	Yamada, S., Suzuki, Y., Suzuki, T., Le, M., Sakai-Tagawa, Y., Muramoto, Y., Ito, M., Kiso, M., Horimoto, T., Shinya, K., Sawada, T., Kiso, M., Usui, T., Murata, T., Lin, Y., Hay, A., Haire, L., Stevens, D., Russell, R., Gamblin, S., Skehel, J. and Kawaoka, Y. (2006) Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature, 444, 378-382. doi:10.1038/nature05264
[27]	Kasson, P., Ensign, D. and Pande, V. (2009) Combining molecular dynamics with Bayesian analysis to predict evaluate ligand-binding mutations in influenza hemagglutinin. Journal of the American Chemical Society, 131, 11339-11340. doi:10.1021/ja904557w
[28]	Stevens, J., Blixt, O., Tumpey, T., Taubenberger, J.K., Paulson, J. and Wilson, I. (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science, 312, 404-410.
[29]	Brooks, B., Brooks, C.L. III, Mackerell, A., Nilsson, L., Peterealla, R., Roux, B., Won, Y. and Archontis, G., et al. (2009) CHARMM: The biomolecular simulation program. Journal of Computational Chemistry, 30, 1545- 1614. doi:10.1002/jcc.21287
[30]	Rapaport, D.C. (2004) The art of molecular dynamics simulation. 2nd Edition, Cambridge University Press, Cambridge. doi:10.1017/CBO9780511816581
[31]	Chothia, C. and Lesk, A.M. (1987) Canonical structures for the hypervariable regions of immunoglobulins. Journal of Molecular Modeling, 196, 901-917. doi:10.1016/0022-2836(87)90412-8
[32]	Ndifon, W., Wingreen, N.S., Levin, S.A. (2009) Differ- ential neutralization efficiency of hemagglutinin epitopes, antibody interference, and the design of influenza vac- cines. Proceedings of the National Academy of Sciences, 106, 8701-8706.