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

Abstract

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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Abbreviations

GNA:

Galanthus nivalis agglutinin

TGL:

Tulipa gesneriana lectin

YFL-II:

Yucca filamentosa lectin

YFL-I:

Yucca filamentosa lectin

3D-QSAR:

Three-dimensional quantitative structure–activity relationship

AMLa :

Arum maculatum lectin

AAL:

Arisaema amurense lectin

PLC:

Pinellia cordata lectin

AMLb :

Alocasia macrorrhiza lectin

PTL:

Pinellia ternata lectin

PCL:

Polygonatum cyrtonema lectin

AHL:

Arisaema heterophyllum lectin

HA:

Hemagglutinin

HA-I:

1934 Human H1 HA

HA-II:

1918 Human H1 HA

vRNP:

Viral nucleoprotein

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Acknowledgments

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Fig. S1
figure7

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
figure8

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
figure9

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
figure10

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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Keywords

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