Molecular modeling, docking and dynamics simulations of GNA-related lectins for potential prevention of influenza virus (H1N1)


The Galanthus nivalis agglutinin (GNA)-related lectin family exhibit significant anti-HIV and anti-HSV properties that are closely related to their carbohydrate-binding activities. However, there is still no conclusive evidence that GNA-related lectins possess anti-influenza properties. The hemagglutinin (HA) of influenza virus is a surface protein that is involved in binding host cell sialic acid during the early stages of infection. Herein, we studied the 3D-QSARs (three-dimensional quantitative structure–activity relationships) of lectin– and HA–sialic acid by molecular modeling. The affinities and stabilities of lectin– and HA–sialic acid complexes were also assessed by molecular docking and molecular dynamics simulations. Finally, anti-influenza GNA-related lectins that possess stable conformations and higher binding affinities for sialic acid than HAs of human influenza virus were screened, and a possible mechanism was proposed. Accordingly, our results indicate that some GNA-related lectins, such as Yucca filamentosa lectin and Polygonatum cyrtonema lectin, could act as drugs that prevent influenza virus infection via competitive binding. In conclusion, the GNA-related lectin family may be helpful in the design of novel candidate agents for preventing influenza A infection through the use of competitive combination against sialic acid specific viral infection.

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Galanthus nivalis agglutinin


Tulipa gesneriana lectin


Yucca filamentosa lectin


Yucca filamentosa lectin


Three-dimensional quantitative structure–activity relationship

AMLa :

Arum maculatum lectin


Arisaema amurense lectin


Pinellia cordata lectin

AMLb :

Alocasia macrorrhiza lectin


Pinellia ternata lectin


Polygonatum cyrtonema lectin


Arisaema heterophyllum lectin




1934 Human H1 HA


1918 Human H1 HA


Viral nucleoprotein


  1. 1.

    Goldstein IJ, Hughes RC, Monsigny T, Osawa T, Sharon N (1980) What should be called a lectin? Nature 285:66

  2. 2.

    Sharon N, Lis H (1989) Lectins as cell recognition molecules. Science 246:227–234

  3. 3.

    Liu B, Bian HJ, Bao JK (2010) Plant lectins: potential antineoplastic drugs from bench to clinic. Cancer Lett 287:1–12

  4. 4.

    Balzarini J (2007) Targeting the glycans of glycoproteins: a novel paradigm for antiviral therapy. Nat Rev Microbiol 5:583–597

  5. 5.

    Liu B, Zhang B, Min MW, Bian HJ, Chen LF, Liu Q, Bao JK (2009) Induction of apoptosis by Polygonatum odoratum lectin and its molecular mechanisms in murine fibrosarcoma L929 cells. Biochim Biophys Acta 1790:840–844

  6. 6.

    Liu B, Cheng Y, Zhang B, Bian HJ, Bao JK (2009) Polygonatum cyrtonema lectin induces apoptosis and autophagy in human melanoma A375 cells through a mitochondria-mediated ROS-p38-p53 pathway. Cancer Lett 275:54–60

  7. 7.

    Liu B, Cheng Y, Bian HJ, Bao JK (2009) Molecular mechanisms of Polygonatum cyrtonema lectin-induced apoptosis and autophagy in cancer cells. Autophagy 5:253–255

  8. 8.

    Li CY, Meng L, Liu B, Bao JK (2009) Galanthus nivalis agglutinin (GNA)-related lectins: traditional proteins, burgeoning drugs? Curr Chem Biol 3:324–333

  9. 9.

    An J, Liu JZ, Wu CF, Li J, Dai L, van Damme E, Balzarini J, De Clercq E, Chen F, Bao JK (2006) Anti-HIV I/II activity and molecular cloning of a novel mannose/sialic acid-binding lectin from rhizome of Polygonatum cyrtonema Hua. Acta Biochim Biophys Sin (Shanghai) 38:70–78

  10. 10.

    Tian Q, Wang W, Miao C, Peng H, Liu B, Leng FW, Dai L, Chen F, Bao JK (2008) Purification, characterization and molecular cloning of a novel mannose-binding lectin from rhizomes of Ophiopogon japonicus with antiviral and antifungal activities. Plant Sci 175:877–884

  11. 11.

    Liu J, Stevens DJ, Haire LF, Walker PA, Coombs PJ, Russell RJ, Gamblin SJ, Skehel JJ (2009) Structures of receptor complexes formed by hemagglutinins from the Asian Influenza Pandemic of 1957. Proc Natl Acad Sci USA 106:17175–17180

  12. 12.

    Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, Vasisht N, Steinhauer DA, Daniels RS, Elliot A, Wiley DC, Skehel JJ (2004) The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303:1838–1842

  13. 13.

    Lin T, Wang G, Li A, Zhang Q, Wu C, Zhang R, Cai Q, Song W, Yuen KY (2009) The hemagglutinin structure of an avian H1N1 influenza A virus. Virology 392:73–81

  14. 14.

    Russell RJ, Stevens DJ, Haire LF, Gamblin SJ, Skehel JJ (2006) Avian and human receptor binding by hemagglutinins of influenza A viruses. Glycoconj J 23:85–92

  15. 15.

    Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569

  16. 16.

    Cohen J (2010) Swine flu pandemic. What’s old is new: 1918 virus matches 2009 H1N1 strain. Science 327:1563–1564

  17. 17.

    Chandrasekaran A, Srinivasan A, Raman R, Viswanathan K, Raguram S, Tumpey TM, Sasisekharan V, Sasisekharan R (2008) Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nat Biotechnol 26:107–113

  18. 18.

    Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404–410

  19. 19.

    van Riel D, Munster VJ, de Wit E, Rimmelzwaan GF, Fouchier RA, Osterhaus AD, Kuiken T (2007) Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am J Pathol 171:1215–1223

  20. 20.

    Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Avian flu: influenza virus receptors in the human airway. Nature 440:435–436

  21. 21.

    Nicholls JM, Bourne AJ, Chen H, Guan Y, Peiris JS (2007) Sialic acid receptor detection in the human respiratory tract: evidence for widespread distribution of potential binding sites for human and avian influenza viruses. Respir Res 8:73

  22. 22.

    van Damme EJ, Nakamura-Tsuruta S, Smith DF, Ongenaert M, Winter HC, Rougé P, Goldstein IJ, Mo H, Kominami J, Culerrier R, Barre A, Hirabayashi J, Peumans WJ (2007) Phylogenetic and specificity studies of two-domain GNA-related lectins: generation of multispecificity through domain duplication and divergent evolution. Biochem J 404:51–61

  23. 23.

    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

  24. 24.

    de Castro E, Sigrist CJ, Gattiker A, Bulliard V, Langendijk-Genevaux PS, Gasteiger E, Bairoch A, Hulo N (2006) ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins. Nucleic Acids Res 34:W362–W365

  25. 25.

    Martí-Renom MA, Stuart AC, Fiser A, Sánchez R, Melo F, Sali A (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291–325

  26. 26.

    Wright CS, Hester G (1996) The 2.0 A structure of a cross-linked complex between snowdrop lectin and a branched mannopentaose: evidence for two unique binding modes. Structure 4:1339–1352

  27. 27.

    Lang PT, Brozell SR, Mukherjee S, Pettersen EF, Meng EC, Thomas V, Rizzo RC, Case DA, James TL, Kuntz ID (2009) DOCK 6: combining techniques to model RNA–small molecule complexes. RNA 15:1219–1230

  28. 28.

    van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718

  29. 29.

    van Gunsteren WF, Billeter SR, Eising AA, Hünenberger PH, Krüger P, Mark AE, RP SW, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide. Hochschulverlag AG, Zurich, ISBN 3 7281 2422 2

  30. 30.

    Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) Interaction models for water in relation to protein hydration. Intermolecular Forces 11:331–342

  31. 31.

    Schüttelkopf AW, van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr D 60:1355–1363

  32. 32.

    Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N log (N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

  33. 33.

    Essmann U, Perera L, Berkowitz ML (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8592

  34. 34.

    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

  35. 35.

    Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3584–3590

  36. 36.

    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

  37. 37.

    Liu B, Peng H, Yao Q, Li J, Van Damme E, Balzarini J, Bao JK (2009) Bioinformatics analyses of the mannose-binding lectins from Polygonatum cyrtonema, Ophiopogon japonicus and Liparis noversa with antiproliferative and apoptosis-inducing activities. Phytomedicine 16:601–608

  38. 38.

    Liu B, Xu XC, Cheng Y, Huang J, Liu YH, Liu Z, Min MW, Bian HJ, Chen J, Bao JK (2008) Apoptosis-inducing effect and structural basis of Polygonatum cyrtonema lectin and chemical modification properties on its mannose-binding sites. BMB Rep 41:369–375

  39. 39.

    Ding J, Bao J, Zhu D, Zhang Y, Wang DC (2010) Crystal structures of a novel anti-HIV mannose-binding lectin from Polygonatum cyrtonema Hua with unique ligand-binding property and super-structure. J Struct Biol 171:309–317

  40. 40.

    Okimoto N, Futatsugi N, Fuji H, Suenaga A, Morimoto G, Yanai R, Ohno Y, Narumi T, Taiji M (2009) High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations. PLoS Comput Biol 5:e1000528

  41. 41.

    Newhouse EI, Xu D, Markwick PR, Amaro RE, Pao HC, Wu KJ, Alam M, McCammon JA, Li WW (2009) Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective. J Am Chem Soc 131:17430–17442

  42. 42.

    Alonso H, Bliznyuk AA, Gready JE (2006) Combining docking and molecular dynamic simulations in drug design. Med Res Rev 26:531–568

  43. 43.

    Balzarini J (2006) Inhibition of HIV entry by carbohydrate-binding proteins. Antivir Res 71:237–247

  44. 44.

    Balzarini J, Schols D, Neyts J, van Damme E, Peumans W, de Clercq E (1991) Alpha-(1–3)- and alpha-(1–6)-D-mannose-specific plant lectins are markedly inhibitory to human immunodeficiency virus and cytomegalovirus infections in vitro. Antimicrob Agents Chemother 35:410–416

  45. 45.

    Chand P, Bantia S, Kotian PL, El-Kattan Y, Lin TH, Babu YS (2005) Comparison of the anti-influenza virus activity of cyclopentane derivatives with oseltamivir and zanamivir in vivo. Bioorg Med Chem 13:4071–4077

  46. 46.

    von Itzstein M (2007) The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 6:967–974

  47. 47.

    Yu K, Luo C, Qin G, Xu Z, Li N, Liu H, Shen X, Ma J, Wang Q, Yang C, Zhu W, Jiang H (2009) Why are oseltamivir and zanamivir effective against the newly emerged influenza A virus (A/H1N1)? Cell Res 19:1221–1224

  48. 48.

    Wang CC, Chen JR, Tseng YC, Hsu CH, Hung YF, Chen SW, Chen CM, Khoo KH, Cheng TJ, Cheng YS, Jan JT, Wu CY, Ma C, Wong CH (2009) Glycans on influenza hemagglutinin affect receptor binding and immune response. Proc Natl Acad Sci USA 106:18137–18142

  49. 49.

    Xu R, Ekiert DC, Krause JC, Hai R, Crowe JE Jr, Wilson IA (2010) Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328:357–360

  50. 50.

    Shriver Z, Raman R, Viswanathan K, Sasisekharan R (2009) Context-specific target definition in influenza a virus hemagglutinin–glycan receptor interactions. Chem Biol 16:803–814

  51. 51.

    Ludwig S, Planz O, Pleschka S, Wolff T (2003) Influenza-virus-induced signaling cascades: targets for antiviral therapy? Trends Mol Med 9:46–52

  52. 52.

    Ludwig S, Planz O, Pleschka S, Wolff T (2008) Signaling to life and death: influenza viruses and intracellular signal transduction cascades. In: Klenk HD, Matrosovich MN, Stech J (eds) Avian influenza. Basel, Karger, pp 210–224

  53. 53.

    Ludwig S (2009) Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy. J Antimicrob Chemother 64:1–4

  54. 54.

    Ehrhardt C, Wolff T, Pleschka S, Planz O, Beermann W, Bode JG, Schmolke M, Ludwig S (2007) Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J Virol 81:3058–3067

  55. 55.

    Ehrhardt C, Ludwig S (2009) A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway. Cell Microbiol 11:863–871

  56. 56.

    Liu B, Wu JM, Li J, Liu JJ, Li WW, Li CY, Xu HL, Bao JK (2010) Polygonatum cyrtonema lectin induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras-Raf and PI3K-Akt signaling pathways. Biochimie 92:1934–1938

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We are grateful to Miss Mingwei Min (University of Cambridge) and Qian Liu (National University of Singapore) for their critical reviews of this manuscript. This work was supported in part by grants from the National Natural Science Foundation of China (General Programs: no. 30670469 and no. 30970643).

Author information

Correspondence to Jin-ku Bao.

Additional information

Huai-long Xu and Chun-yang Li contributed equally to this work

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Fig. S1

Sequences of 51 potential sialic acid-binding GNA-related lectins. Conserved ‘QXDXNXVXY’ motif of GNA-related lectins plays a crucial role in this mannose recognition, whereas, sialic acid binding activities of GNA-related lectins might result from the amino acid mutation of conservative mannose-binding motif of GNA-related lectins (GIF 1040 kb)

Fig. S2

The overall modeling of GNA-related lectins in complex with sialic acid. (A) YFL-II lectin, the first binding type of GNA-related lectin, in complex with sialic acid. (B-F) The second binding type of GNA-related lectin-sialic acid complexes including AHL-sialic acid (B), AMLb-sialic acid (C), PCL-sialic acid (D), PLC-sialic acid (E) and PTL-sialic acid (F) complexes (GIF 344 kb)

Fig. S3

Secondary structure variations of proteins (GNA-related lectins and HAs)-sialic acid complexes by molecular dynamics simulation. Secondary structure variations over time for the 1918 Human H1 HA-sialic acid (A), TGL-sialic acid (B), YFL-II-sialic acid (C), AAL-sialic acid (D), AHL-sialic acid (E), AMLb-sialic acid (F), PCL-sialic acid (G), PLC-sialic acid (H) and PTL-sialic acid (I) complexes (GIF 162 kb)

Fig. S4

Hydrogen-bond variations of proteins (GNA-related lectins and HAs)-sialic acid complexes by molecular dynamics simulation. Hydrogen-bond variations over time for the 1918 Human H1 HA-sialic acid (A), TGL-sialic acid (B), YFL-II-sialic acid (C), AAL-sialic acid (D), AHL-sialic acid (E), AMLb-sialic acid (F), PCL-sialic acid (G), PLC-sialic acid (H) and PTL-sialic acid (I) complexes (GIF 70 kb)

Motions of YFL-I-sialic acid complex during simulation time. Yucca filamentosa lectin has been abbreviated as YFL-I (MPG 1262 kb)

Motions of HA-I-sialic acid complex during simulation time. 1934 Human H1 HA has been abbreviated as HA-I (MPG 726 kb)

High resolution image file (TIFF 3907 kb)

High resolution image file (TIFF 10159 kb)

High resolution image file (TIFF 1673 kb)

High resolution image file (TIFF 6146 kb)

Video S1

Motions of YFL-I-sialic acid complex during simulation time. Yucca filamentosa lectin has been abbreviated as YFL-I (MPG 1262 kb)

Video S2

Motions of HA-I-sialic acid complex during simulation time. 1934 Human H1 HA has been abbreviated as HA-I (MPG 726 kb)

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Xu, H., Li, C., He, X. et al. Molecular modeling, docking and dynamics simulations of GNA-related lectins for potential prevention of influenza virus (H1N1). J Mol Model 18, 27–37 (2012) doi:10.1007/s00894-011-1022-7

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  • Galanthus nivalis agglutinin (GNA)-related lectins
  • Hemagglutinin (HA)
  • Influenza A virus
  • Polygonatum cyrtonema lectin (PCL)
  • Viral infection