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Two glycosylation sites in H5N1 influenza virus hemagglutinin that affect binding preference by computer-based analysis.

Chen W, Sun S, Li Z - PLoS ONE (2012)

Bottom Line: Two glycosylation sites, 158N and 169N, also participate in receptor recognition.As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs.The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, People's Republic of China.

ABSTRACT
Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor-binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.

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The dynamical properties of the HA models during MD simulation.(A) Six convergent RMSDs of the HA models indicate the stable states, while highly glycosylated HAs experienced larger fluctuation against the initial conformations. (B) The RMSF values reflect the fluctuation of those residues in the RBD. The S227N mutation in 03HK would result in a relatively stable 222Lys (with a lower RMSF value in 222). The glycans at 158N of affect their acroteric amino-acid residues. (C) The RMSF of the three glycans on HM, DS, and FG present the complicated praxiology that the glycan residues in the core are more stable compared with the terminal glycan residues. Columns 2–5 represent the RMSF in the core of the N-glycan compared with the glycan residues at the branches and terminus.
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pone-0038794-g005: The dynamical properties of the HA models during MD simulation.(A) Six convergent RMSDs of the HA models indicate the stable states, while highly glycosylated HAs experienced larger fluctuation against the initial conformations. (B) The RMSF values reflect the fluctuation of those residues in the RBD. The S227N mutation in 03HK would result in a relatively stable 222Lys (with a lower RMSF value in 222). The glycans at 158N of affect their acroteric amino-acid residues. (C) The RMSF of the three glycans on HM, DS, and FG present the complicated praxiology that the glycan residues in the core are more stable compared with the terminal glycan residues. Columns 2–5 represent the RMSF in the core of the N-glycan compared with the glycan residues at the branches and terminus.

Mentions: The individual RMSFs in the RBD showed significant difference. Those relatively active residues, which have a higher RMSF and less impacted by steric clashes, may change their conformation to accommodate the receptors. During the 16 ns MD simulations, the energetic and structural properties were monitored for the 6 systems. The RMSDs and the energies converged in all of the systems, which indicated well-behaved simulations (Figure 5A). We found that the helical structure and the overall protein backbones were stable during the whole equilibrium, whereas the loop experienced larger fluctuations relatively. Loop220 may fluctuate more than Loop130 and Helix190, based on their respective RMSFs. Considering the results from the phylogenetic analysis, four most conserved residues, 95Tyr, 153Trp, 183His and 195Tyr, located at the bottom of the RBD, had lower RMSFs compare with the non-conserved residues (Figure 5B). By analyzing the MD trajectories, the replaced residues in 03HK would affect their acroteric amino-acid residues. The RMSF of 222Lys in 03HK decreased, which was responsible for the interaction of the basic group in 222Lys with the newly introduced, weakly acidic amide group of the S227N residue, a motion that made the two sides of Loop220 become closer. Moreover, by changing S159N and T160A in 03HK, the RMSFs of the adjacent residues were also changed, which indicated the steric alteration.


Two glycosylation sites in H5N1 influenza virus hemagglutinin that affect binding preference by computer-based analysis.

Chen W, Sun S, Li Z - PLoS ONE (2012)

The dynamical properties of the HA models during MD simulation.(A) Six convergent RMSDs of the HA models indicate the stable states, while highly glycosylated HAs experienced larger fluctuation against the initial conformations. (B) The RMSF values reflect the fluctuation of those residues in the RBD. The S227N mutation in 03HK would result in a relatively stable 222Lys (with a lower RMSF value in 222). The glycans at 158N of affect their acroteric amino-acid residues. (C) The RMSF of the three glycans on HM, DS, and FG present the complicated praxiology that the glycan residues in the core are more stable compared with the terminal glycan residues. Columns 2–5 represent the RMSF in the core of the N-glycan compared with the glycan residues at the branches and terminus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375263&req=5

pone-0038794-g005: The dynamical properties of the HA models during MD simulation.(A) Six convergent RMSDs of the HA models indicate the stable states, while highly glycosylated HAs experienced larger fluctuation against the initial conformations. (B) The RMSF values reflect the fluctuation of those residues in the RBD. The S227N mutation in 03HK would result in a relatively stable 222Lys (with a lower RMSF value in 222). The glycans at 158N of affect their acroteric amino-acid residues. (C) The RMSF of the three glycans on HM, DS, and FG present the complicated praxiology that the glycan residues in the core are more stable compared with the terminal glycan residues. Columns 2–5 represent the RMSF in the core of the N-glycan compared with the glycan residues at the branches and terminus.
Mentions: The individual RMSFs in the RBD showed significant difference. Those relatively active residues, which have a higher RMSF and less impacted by steric clashes, may change their conformation to accommodate the receptors. During the 16 ns MD simulations, the energetic and structural properties were monitored for the 6 systems. The RMSDs and the energies converged in all of the systems, which indicated well-behaved simulations (Figure 5A). We found that the helical structure and the overall protein backbones were stable during the whole equilibrium, whereas the loop experienced larger fluctuations relatively. Loop220 may fluctuate more than Loop130 and Helix190, based on their respective RMSFs. Considering the results from the phylogenetic analysis, four most conserved residues, 95Tyr, 153Trp, 183His and 195Tyr, located at the bottom of the RBD, had lower RMSFs compare with the non-conserved residues (Figure 5B). By analyzing the MD trajectories, the replaced residues in 03HK would affect their acroteric amino-acid residues. The RMSF of 222Lys in 03HK decreased, which was responsible for the interaction of the basic group in 222Lys with the newly introduced, weakly acidic amide group of the S227N residue, a motion that made the two sides of Loop220 become closer. Moreover, by changing S159N and T160A in 03HK, the RMSFs of the adjacent residues were also changed, which indicated the steric alteration.

Bottom Line: Two glycosylation sites, 158N and 169N, also participate in receptor recognition.As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs.The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, People's Republic of China.

ABSTRACT
Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor-binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-α-2,3-Gal and SA-α-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-α-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-α-2,3-Gal analogs.

Show MeSH
Related in: MedlinePlus