Pathogenicity characterization with implicit and explicit molecular dynamics simulation
Sigit Jaya Herlambang, Rosari Saleh
DOI: 10.4236/ns.2011.312127   PDF    HTML     4,265 Downloads   7,878 Views  


The contribution of water molecules in molecular dynamics simulation (MDS) is unquestionably high, particularly for enzymatic interaction which occurred in the cytoplasmic environment. The addition of water molecules to the system will surely influence different direct interaction between active site residues and substrate. We try to theoretically investigate to what extent the pathogenicity characterization will varies in different neuraminidase-sialic acid complex systems. The heating dynamics simulations were produced with and without TIP3P water molecules. The periodic boundary system was made for explicitly added TIP3P water molecules and generalized born molecular volume (GBMV) energy contribution was added for implicit solvent system. Both complexes, neuraminidasesialic acid of A/Tokyo/3/67 and A/Pennsylvania/10218/ 84, which have a different pathogenicity levels were minimized and simulated. The result shows more residues produced hydrogen bonds with substrate when water molecules were not added to the system. The binding free energies also show differences. Overall, even the values of energy differences, but an implicit solvent provides the similar result (HPAI complex has higher activity than LPAI for both systems) in characterization of pathogenic virus neuraminidase activity.

Share and Cite:

Herlambang, S. and Saleh, R. (2011) Pathogenicity characterization with implicit and explicit molecular dynamics simulation. Natural Science, 3, 1022-1028. doi: 10.4236/ns.2011.312127.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Russell, R.J., Haire, L.F., Stevens, D.J., Collins, P.J., Lin, Y.P., Blackburn, G.M., Hay, A.J., Gamblin, S.J. and Ske- hel, J.J. (2006) The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug de- sign. Nature, 443, 45-49. doi:10.1038/nature05114
[2] Chachra, R. and Rizzo, R.C. (2008) Origins of resistance conferred by the R292K neuraminidase mutation via molecular dynamics and free energy calculations. Jour- nal of Chemical Theory and Computation, 4, 1526-1540. doi:10.1021/ct800068v
[3] McKimm-Breschkin, J.L., Sahasrabudhe, A., Blick, T.J., McDonald, M., Colman, P.M., Hart, G.J., Bethell, R.C. and Varghese, J.N. (1998) Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en derivatives. Journal of Virology, 72, 2456-2462.
[4] Mishin, V.P., Hayden, F.G. and Gubareva, L.V. (2005) Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrobial Agents and Chemotherapy, 49, 4515-4520. doi:10.1128/AAC.49.11.4515-4520.2005
[5] Sheu, T.G., Deyde, V.M., Okomo-Adhiambo, M., Garten, R.J., Xu, X., Bright, R.A., Butler, E.N., Wallis, T.R., Klimov, A.I. and Gubareva, L.V. (2008) Surveillance for neuraminidase inhibitor resistance among human influ- enza A and B viruses circulating worldwide from 2004 to 2008. Antimicrobial Agents and Chemotherapy, 52, 3284- 3292.
[6] Wetherall, N.T., Trivedi, T., Zeller, J., Hodges-Savola, C., McKimm-Breschkin, J.L., Zambon, M. and Hayden, F.G. (2003) Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza clinical isolates to neuraminidase inhibitors: Report of the Neuraminidase Inhibitor Susceptibility Network. Journal of Clinical Microbiology, 41, 742-750. doi:10.1128/JCM.41.2.742-750.2003
[7] McKimm-Breschkin, J.L., Trivedi, T., Hampson, A., Hay, A., Klimov, A., Tashiro, M., Hayden, F.G. and Zambon, M. (2003) Neuraminidase sequence analysis and suscep- tibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrobial Agents and Chemotherapy, 47, 2264-2272. doi:10.1128/AAC.47.7.2264-2272.2003
[8] Yen, H., Ilyushina, N.A., Salomon, R., Hoffmann, E., Webster, R.G. and Govorkova, E.A. (2007) Neuramini- dase inhibitor-resistant recombinant a/vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. Journal of Virology, 81, 12418-12426. doi:10.1128/JVI.01067-07
[9] Meijer, A., Lackenby, A., Hungnes, O., Lina, B., van der Werf, S., Schweiger, B., Opp, M., Paget, J., van de Kassteele, J., Hay, J. and Zambon. M. (2009) Osel- tamivir-resistant influenza virus A (H1N1), Europe, 2007- 08 Season. Emerging Infectious Diseases, 15, 552-560. doi:10.3201/eid1504.081280
[10] Monto, A.S., McKimm-Breschkin, J.L., Macken, C., Hampson, A.W., Hay, A., Klimov, A., Tashiro, M., Web- ster, R.G., Aymard, M., Hayden, F.G. and Zambon, M. (2006) Detection of influenza viruses resistant to neural- minidase inhibitors in global surveillance during the first 3 years of their use. Antimicrobial Agents and Chemo- therapy, 50, 2395-2402. doi:10.1128/AAC.01339-05
[11] Tamura, D., Mitamura, K., Yamazaki, M., Fujino, M., Nirasawa, M., Kimura, K., Kiso, M., Shimizu, H., Ka- wakami, C., Hiroi, S., Takahashi, S., Hata, M., Minagawa, H., Kimura, Y., Kaneda, S., Sugita, S., Horimoto, T., Sugaya, N. and Kawaoka, Y. (2009) Oseltamivir-resistant influenza A viruses circulating in Japan. Journal of Clinical Microbiology, 47, 1424-1427. doi:10.1128/JCM.02396-08
[12] Lee, M.S., Feig, M., Salsbury, F. R. and Brooks, C.L.III. (2003) New analytic approximation to the standard mo- lecular volume definition and its application to genera- lized born calculations. Journal of Computational Che- mistry, 24, 1348-1356. doi:10.1002/jcc.10272
[13] Pereira, M.S., Chakraverty, P. and Pane, A.R. (1969) The influence of antigenic variation on influenza A2 epidem- ics. Journal of Hygiene, 67, 551-557.
[15] Kaverin, N.V., Rudneva, I.A., Ilyushina, N.A., Varich, N.L., Lipatov, A.S., Smirnov, Y.A., Govorkova, E.A., Gitelman, A.K., Lvov, D.K. and Webster, R.G. (2002) Structure of antigenic sites on the haemagglutinin mole- cule of H5 avian influenza virus and phenotypic variation of escape mutants. Journal of General Virology, 83, 2497-2505.
[16] Varghese, J.N., Mc-Kimm-Breschkin, J.L., Caldwell, J.B., Kortt, A.A. and Colman, P.M., (1992) The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins, 14, 327-332. doi:10.1002/prot.340140302
[18] Brooks, B.R., Bruccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M. (1983) CHARMM: A program for macromolecular energy minimization and dynamics calculations. Journal of Computational Chem- istry, 4, 187-217. doi:10.1002/jcc.540040211
[19] Brooks et al., (2009) CHARMM: The biomolecular simulation program. Journal of Computational Chemis- try, 30, 1545-1614. doi:10.1002/jcc.21287
[20] Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W. and Klein, M.L. (1983) Comparison of simple potential functions for simulating liquid water. Journal of Chemical Physics, 79, 926-935. doi:10.1063/1.445869
[21] Brooks, C.L.III, Pettit, B.M. and Karplus, M. (1985) Structural and energetic effects of truncating long ranged interactions in ionic and polar fluids. Journal of Chemi- cal Physics, 83, 5897-5908. doi:10.1063/1.449621
[22] Steinbach, P.J. and Brooks, B.R. (1994) New sphere- cal-cutoff methods for long-range forces in macromo- lecular simulation. Journal of Computational Chemistry, 15, 667-683. doi:10.1002/jcc.540150702
[23] Shu, M., Lin, Z., Zhang, Y., Wu, Y., Mei, H. and Jiang, Y. (2010) Molecular dynamics simulation of oseltamivir resistance in neuraminidase of avian influennza H5N1 virus. Journal of Molecular Modeling, 17, 587-592.
[24] Amaro, R.E., Cheng, X., Ivanov, I., Xu, D. and McCammon, J.A. (2009) Characterizing loop dynamics and ligand recognition in human- and avian-type influ- enza neuraminidases via generalized born molecular dynamics and end-point free energy calculations. Journal of the American Chemical Society, 13, 4702-4709. doi:10.1021/ja8085643
[25] Masukawa, K.M., Kollman, P.A. and Kuntz, I.D. (2003) Investigation of neuraminidase-substrate recognition using molecular dynamics and free energy calculations. Journal of Medicinal Chemistry, 46, 5628-5637. doi:10.1021/jm030060q
[26] Smith, B.J., Colman, P.M., von itzstein, M., Danylec, B. and Varghese, J.N. (2000) Analysis of inhibitor binding in influenza virus neuraminidase. Protein Science, 10, 689-696. doi:10.1110/ps.41801
[27] Guo, X.L., Wei, D.Q., Zhul, Y.S. and Chou, K.C., (2008) Cleavage mechanism of the H5N1 hemagglutinin by trypsin and furin. Amino Acids, 35, 375-382.
[28] Decha, P., Rungrotmongkol, T., Intharathep, P., Malaisree, M., Aruksakunwong, O., Laohpongspaisan, C., Parasuk, V., Sompornpisut, P., Pianwanit, S., Kokpol, S. and Hannongbua, S. (2008) Source of high pathogenicity of an avian influenza virus H5N1: Why H5 is better cleaved by furin. Biophysical Journal, 95, 128-134. doi:10.1529/biophysj.107.127456
[29] Aruksakunwong, O., Malisree, M., Decha, P., Sompornpisut, P., Parasuk, V., Pianwanit, S. and Hannongbua, S. (2007) On the lower susceptibility of oseltamivir to influenza neuraminidase subtype than those in N2 and N9. Biophysical Journal, 92, 798-807. doi:10.1529/biophysj.106.092528
[30] Le, L., Lee, E., Schulten, K. and Truong, T.N. (2009) Molecular modeling of swine influenza A/H1N1, Spanish H1N1, and avian H5N1 flu N1 neuraminidases bound to tamiflu and relenza. PloS Current,
[31] von Itzstein, M., Wu, W.Y., Kok, G.B., Pegg, M.S., Dyason, J.C., Jin, B., Phan, T.V., Smythe, M.L., White, H.F., Oliver, S.W., Colman, P.M., Varghese, J.N., Ryan, D.M., Woods, J.M., Bethell, R.C., Hotham, V.J., Cameron, J.M. and Penn, C.R. (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature, 363, 418-423. doi:10.1038/363418a0

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.