Glycoconjugate Journal

, Volume 31, Issue 5, pp 365–386 | Cite as

Molecular dynamics study of the conformations of glycosidic linkages in sialic acid modified ganglioside GM3 analogues

  • G. Jaishree
  • D. Jeya Sundara Sharmila


The objective of the present study is to model the analogues of monosialoganglioside (GM3) by making modifications in its sialic acid residue with different substitutions in aqueous environment and to determine their structural stability based upon computational molecular dynamics. Molecular mechanics and molecular dynamics investigation was carried out to study the conformational preferences of the analogues of GM3. Dynamic simulations were carried out on the analogues of GM3 varying in the substituents at C-1, C-4, C-5, C-8 and C-9 positions of their sialic acid or Neuraminic acid (NeuAc) residue. The analogues are soaked in a periodic box of TIP3P water as solvent and subjected to a 10 ns molecular dynamics (MD) simulation using AMBER ff03 and gaff force fields with 30 ps equilibration. The analogue of GM3 with 9-N-succNeuAc (analogue5, C9 substitution) was observed to have the lowest energy of −6112.5 kcal/mol. Graphical analysis made on the MD trajectory reveals the direct and water mediated hydrogen bonds existing in these sialic acid analogues. The preferable conformations for glycosidic linkages of GM3 analogues found in different minimum energy regions in the conformational maps were identified. This study sheds light on the conformational preferences of GM3 analogues which may be essential for the design of GM3 analogues as inhibitors for different ganglioside specific pathogenic proteins such as bacterial toxins, influenza toxins and neuraminidases.


Ganglioside GM3 analogues AMBER Molecular Modeling Molecular Mechanics Molecular Dynamics 



The authors acknowledge the Science and Engineering Research Board (SERB), Department of Science and Technology, Govt. of India (SERB Sanction no. SR/FT/LS-157/2009 dt 30.04.2012) - OYS scheme project grant sanctioned to the corresponding author.


  1. 1.
    Bacia, K., Scherfeld, D., Kahya, N., Schwille, P.: Fluorescence correlation spectroscopy relates rafts in model and native membranes. Biophys. J. 87, 1034–1043 (2004)PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Huwiler, A., Kolter, T., Pfeilschifter, J., Sandhoff, K.: Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim. Biophys. Acta 1485, 63–99 (2000)PubMedCrossRefGoogle Scholar
  3. 3.
    Leeden, R.W., Yu, R.K.: Gangliosides: Structure, isolation and analysis. Methods Enzymol. 83, 139–191 (1982)CrossRefGoogle Scholar
  4. 4.
    Ishida, H., Kiso, M.: Chemical synthesis of bioactive oligosaccharides. systematic syntheses of gangliosides. Trends Glycosci. Glycotech. 13, 57–64 (2001)CrossRefGoogle Scholar
  5. 5.
    McDaniel, R.V., McIntosh, T.J.: X-Ray diffraction studies of the cholera toxin receptor, GM1. BioPhy. J. 49, 94–96 (1986)CrossRefGoogle Scholar
  6. 6.
    Hashiramoto, A., Mizukami, H., Yamashita, T.: Ganglioside GM3 promotes cell migration by regulating MAPKand c-Fos/AP-1. Oncogene 25, 3948–3955 (2006)PubMedCrossRefGoogle Scholar
  7. 7.
    Dyatlovitskaya, E.V., Kandyba, A.G.: Sphingolipids in tumor metastases and angiogenesis. Biochem. Mosc. 71, 347–353 (2006). PMID:16615853CrossRefGoogle Scholar
  8. 8.
    Bada, A.M., Casac, A., Mancebo, A., Fuentes, D., Gonz¡lez, B.: Acute and repeated dose intramuscular toxicity of GM3 cancer vaccine in SD rats. Pak. J. Biol. Sci. 8, 1045–1050 (2005)CrossRefGoogle Scholar
  9. 9.
    Carr, A., Rodriguez, E., Mdel, C.A., Camacho, R., Osorio, M., et al.: Immunotherapy of advanced breast cancer with a heterophilic ganglioside (NeuGcGM3) cancer vaccine. J. Clin. Oncol. 21, 1015–1021 (2003)PubMedCrossRefGoogle Scholar
  10. 10.
    Guthmann, M.D., Castro, M.A., Zinat, G., Venier, C., Koliren, L., et al.: Cellular and humoral immune response to N-Glycolyl-GM3 elicited by prolonged immunotherapy with an anti-idiotypic vaccine in high-risk and metastatic breast cancer patients. J. Immunother. 29, 215–223 (2006)PubMedCrossRefGoogle Scholar
  11. 11.
    Basu, S., Ma, R., Boyle, P.J., Mikulla, B., Bradley, M., et al.: Apoptosis of human carcinoma cells in the presence of potential anti-cancer drugs: III. Treatment of Colo-205 and SKBR3 cells with: Cis -platin, tamoxifen, melphalan, betulinic acid, L-PDMP, L-PPMP, and GD3 ganglioside. Glycoconj. J. 20, 563–577 (2004)PubMedCrossRefGoogle Scholar
  12. 12.
    Oliva, J.P., Valdes, Z., Casaco, A., Pimentel, G., Gonzalez, J., et al.: Clinical evidences of GM3 (NeuGc) ganglioside expression in human breast cancer using the 14 F7 monoclonal antibody labelled with (99 m)Tc. Breast Cancer Res. Treat. 96, 115–121 (2006)PubMedCrossRefGoogle Scholar
  13. 13.
    Nawar, H.F., Arce, S., Russell, M.W., Connell, T.D.: Mucosal adjuvant properties of mutant lt-iia and lt-iib enterotoxins that exhibit altered ganglioside-binding activities. Infect. Immun. 73, 1330–1342 (2005)PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Nawar, H.F., Berenson, C.S., Hajishengallis, G., Takematsu, H., Mandell, L., Clare, R.L., Connell, T.D.: Binding to gangliosides containing N-acetylneuraminic acid is sufficient to mediate the immunomodulatory properties of the nontoxic mucosal adjuvant LT-IIb(T13I). Clin. Vaccine Immunol. 17, 969–978 (2010). PMID:20392887PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Lingwood, C.A.: Glycolipid receptors for verotoxin and helicobacter pylori: role in pathology. Biochim. Biophys. Acta 1455, 375–386 (1999)PubMedCrossRefGoogle Scholar
  16. 16.
    Hugosson, S., Angstrom, J., Olsson, B.M., Bergstrom, J., Fredlund, H., Olcen, P.: Glycosphingolipid binding specificities of Neisseria meningitides and Haemophilus influenza: Detection, isolation and characterization of a binding-active glycosphingolipid from human oropharyngeal epithelium. J. Biochem. 124, 1138–1152 (1998)PubMedCrossRefGoogle Scholar
  17. 17.
    Rolsma, M.D., Kuhlenschmidt, T.B., Gelberg, H.B., Kuhlenschidt, M.S.: Structure and function of a ganglioside receptor for porcine rotavirus. J. Virol. 72, 9079–9091 (1998)PubMedCentralPubMedGoogle Scholar
  18. 18.
    Vengris, V.E., Reynolds Jr., F.H., Hollenberg, M.D., Pitha, P.M.: Interferon action: role of membrane gangliosides. Virology 72, 486–493 (1976)PubMedCrossRefGoogle Scholar
  19. 19.
    Lingwood, C.A.: Shiga toxin receptor glycolipid binding. Pathol. Utility, Methods Mol. Med 73, 165–186 (2003)Google Scholar
  20. 20.
    Li, Y., Li, S., Hasegawa, A., Ishida, H., Kiso, M., et al.: Structural basis for the resistance of tay-sachs ganglioside GM2 to enzymatic degradation. J. Biol. Chem. 274, 10014–10018 (1999)PubMedCrossRefGoogle Scholar
  21. 21.
    Singh, A.K., Harrison, S.H., Schoeniger, J.S.: Gangliosides as receptors for biological toxins: development of sensitive fluoroimmunoassays using ganglioside-bearing liposomes. Analyt. Chem. 72, 6019–6024 (2000)CrossRefGoogle Scholar
  22. 22.
    Bagchi, A., Ghosh, T.C.: Structural and functional characterization of SoxW-a thioredoxin involved in the transport of reductants during sulfur oxidation by the global sulfur oxidation reaction cycle. Res. J. Microbiol. 1, 392–400 (2006)CrossRefGoogle Scholar
  23. 23.
    Bagchi, A., Ghosh, T.C.: Homology modeling and molecular dynamics study of the interactions of SoxY and SoxZ: the central player of biochemical oxidation of sulfur anions in pseudaminobacter salicylatoxidans. Res. J. Microbiol. 2, 569–576 (2007)CrossRefGoogle Scholar
  24. 24.
    Bouarkat, M., Sabeur, S.A., Bouamrane, R.: Investigating the formation of helical states in the process of homopolymer collapse using molecular dynamics simulations. J Applied Sciences 10, 209–214 (2010)CrossRefGoogle Scholar
  25. 25.
    Maftouni, N., Amininasab, M., Kowsari, F.: Molecular dynamics study of nanobio membranes. J Applied Sciences 11, 1062–1065 (2011)CrossRefGoogle Scholar
  26. 26.
    Sharmila, D.J.S., Jaishree, G., Rapheal, V.S.: Ganglioside GM3 analogues as inhibitors for staphylococcal enterotoxin B and endoglycoceramidase II from Rhodococcus Sp. – docking and ADME screening studies. Asian J. Pharma. Hea. Sci 2, 359–369 (2012)Google Scholar
  27. 27.
    Oetke, C., Brossmer, R., Mantey, L.R., Hinderlich, S., Isecke, R., et al.: Versatile biosynthetic engineering of sialic acid in living cells using synthetic sialic acid analogues. J. Biol. Chem. 277, 6688–6695 (2002)PubMedCrossRefGoogle Scholar
  28. 28.
    Sharmila, D.J.S., Veluraja, K.: Monosialogangliosides and their interaction with cholera toxin-investigation by molecular modelling and molecular mechanics. J. Biomol. Struct. Dyn. 21, 591–614 (2004)PubMedCrossRefGoogle Scholar
  29. 29.
    Case, D.A., Darden, T.A., Cheatham, T.E., Simmerling, C.L., Wang, J., et al.: Amber 10: Users’ manual. University of California, San Francisco (2008)Google Scholar
  30. 30.
    Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., et al.: A second generation force field for the simulation of proteins, nucleic acids and organic molecules. J. Am. Chem. Soc. 117(19), 5179–5197 (1995)CrossRefGoogle Scholar
  31. 31.
    Sauter, N.K., Hanson, J.E., Glick, G.D., Brown, J.H., Crowther, R.L., et al.: Binding of influenza virus hemagglutinin to analogs of its cell-surface receptor, sialic acid: analysis by proton nuclear magnetic resonance spectroscopy and X-ray crystallography. Biochemistry 31, 9609–9621 (1992)PubMedCrossRefGoogle Scholar
  32. 32.
    Bianco, A., Brufani, M., Ciabatti, R., Melchioni, C., Pasquali, V.: Neuraminic acid derivatives as anti-influenza drugs. Mol. Online 2, 129–136 (1998). doi: 10.1007/s007830050068 CrossRefGoogle Scholar
  33. 33.
    Brocca, P., Berthault, P., Sonnino, S.: Conformation of the oligosaccharide chain of GM1 ganglioside in a carbohydrate-enriched surface. Biophys. J. 74, 309–318 (1998)PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Sabesan, S., Bock, K., Lemieux, R.U.: The conformational properties of the gangliosides GM2 and GM1 based on 1H- and 13C-NMR studies. Can. J. Chem. 62, 1034–1045 (1984)CrossRefGoogle Scholar
  35. 35.
    Sharmila, D.J.S., Veluraja, K.: Conformations of higher gangliosides and their binding with cholera toxin-investigation by molecular modeling, molecular mechanics, and molecular dynamics. J. Biomol. Struct. Dyn. 23, 641–656 (2006)PubMedCrossRefGoogle Scholar
  36. 36.
    DeMarco, M.L., Woods, R.J.: Atomic-resolution conformational analysis of the GM3 ganglioside in a lipid bilayer and its implications for ganglioside-protein recognition at membrane surfaces. Glycobiol. 19, 344–355 (2009)CrossRefGoogle Scholar
  37. 37.
    Sharrow, S.D., Edmonds, K.A., Goodman, M.A., Novotny, M.V., Stone, M.J.: Thermodynamic consequences of disrupting a water-mediated hydrogen bond network in a protein: pheromone complex. Protein Sci. 14, 249–256 (2005)PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Patel, R.Y., Balaji, P.V.: Characterization of the conformational and orientational dynamics of ganglioside GM1 in a dipalmitoylphosphatidylcholine bilayer by molecular dynamics simulations. Biochim. Biophys. Acta (Biomembranes) 1768, 1628–1640 (2007)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Bioinformatics, School of Biotechnology and Health SciencesKarunya UniversityCoimbatoreIndia

Personalised recommendations