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Comparative structural analysis of haemagglutinin proteins from type A influenza viruses: conserved and variable features.

Righetto I, Milani A, Cattoli G, Filippini F - BMC Bioinformatics (2014)

Bottom Line: We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy.Focusing on H5N1, we found that variation at the receptor binding domain surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.In particular, variation in electrostatic and hydropathy patches can provide molecular evolution markers: intriguing surface charge redistribution characterizing the haemagglutinin receptor binding domains from circulating H5N1 clades 2 and 7 might have contributed to antigenic escape hence to their evolutionary success and spreading.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology and Bioinformatics Unit (MOLBINFO), Department of Biology, University of Padua, via U. Bassi 58/B, 35131, Padova, Italy. irene.righetto@bio.unipd.it.

ABSTRACT

Background: Genome variation is very high in influenza A viruses. However, viral evolution and spreading is strongly influenced by immunogenic features and capacity to bind host cells, depending in turn on the two major capsidic proteins. Therefore, such viruses are classified based on haemagglutinin and neuraminidase types, e.g. H5N1. Current analyses of viral evolution are based on serological and primary sequence comparison; however, comparative structural analysis of capsidic proteins can provide functional insights on surface regions possibly crucial to antigenicity and cell binding.

Results: We performed extensive structural comparison of influenza virus haemagglutinins and of their domains and subregions to investigate type- and/or domain-specific variation. We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy. Focusing on H5N1, we found that variation at the receptor binding domain surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.

Conclusions: Evidence from this work suggests that integrating phylogenetic and serological analyses by extensive structural comparison can help in understanding the 'functional evolution' of viral surface determinants. In particular, variation in electrostatic and hydropathy patches can provide molecular evolution markers: intriguing surface charge redistribution characterizing the haemagglutinin receptor binding domains from circulating H5N1 clades 2 and 7 might have contributed to antigenic escape hence to their evolutionary success and spreading.

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Related in: MedlinePlus

Isopotential contours (top), heat maps (middle) and density plots (bottom) of HA1 subregions. See Figure 1 caption for details. Isopotential contours are plotted at ±2kBT/e.
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Fig3: Isopotential contours (top), heat maps (middle) and density plots (bottom) of HA1 subregions. See Figure 1 caption for details. Isopotential contours are plotted at ±2kBT/e.

Mentions: In order to perform analyses taking into account the influence of ionic strength (I), the spatial distribution of the electrostatic potential was calculated at both I = 0 mM (Coulombic interactions unscreened by counter-ions) and I = 150 mM (physiological), assuming +1/-1 charges for the counter-ions. Prior to electrostatic potential calculations, partial charges and van der Waals radii were assigned with PDB2PQR [25,26]; then, linear Poisson-Boltzmann (PB) equation calculations were carried out by using Adaptive PB Solver (APBS) [27] through Opal web service (see Methods). The spatial distribution of the electrostatic potential was determined for each HA subregion, monomers and trimers, comparing the six available HA structures to identify possible HA-specific signatures. In particular, we focused on the role of charge distribution as visualized by isopotential contours within the tertiary structure and on classifying conservation and divergence among the different HAs. In order to evaluate electrostatic distance (ED) also in a quantitative way, clustering of the spatial distributions of the electrostatic potentials was obtained by WebPIPSA (Protein Interaction Property Similarity Analysis; [28], having the use of Hodgkin and Carbo similarity index (SI) [29] (see Methods). The Carbo SI is sensitive to the shape of the potential being considered but not the magnitude, whereas the Hodgkin SI is sensitive to both shape and magnitude. Therefore, WebPIPSA results obtained using the Hodgkin SI are shown in Figures 1, 2, 3, 4 and 5, and evidence from analyses performed using the Carbo SI is cited to confirm parameter independent data.Figure 1


Comparative structural analysis of haemagglutinin proteins from type A influenza viruses: conserved and variable features.

Righetto I, Milani A, Cattoli G, Filippini F - BMC Bioinformatics (2014)

Isopotential contours (top), heat maps (middle) and density plots (bottom) of HA1 subregions. See Figure 1 caption for details. Isopotential contours are plotted at ±2kBT/e.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4265342&req=5

Fig3: Isopotential contours (top), heat maps (middle) and density plots (bottom) of HA1 subregions. See Figure 1 caption for details. Isopotential contours are plotted at ±2kBT/e.
Mentions: In order to perform analyses taking into account the influence of ionic strength (I), the spatial distribution of the electrostatic potential was calculated at both I = 0 mM (Coulombic interactions unscreened by counter-ions) and I = 150 mM (physiological), assuming +1/-1 charges for the counter-ions. Prior to electrostatic potential calculations, partial charges and van der Waals radii were assigned with PDB2PQR [25,26]; then, linear Poisson-Boltzmann (PB) equation calculations were carried out by using Adaptive PB Solver (APBS) [27] through Opal web service (see Methods). The spatial distribution of the electrostatic potential was determined for each HA subregion, monomers and trimers, comparing the six available HA structures to identify possible HA-specific signatures. In particular, we focused on the role of charge distribution as visualized by isopotential contours within the tertiary structure and on classifying conservation and divergence among the different HAs. In order to evaluate electrostatic distance (ED) also in a quantitative way, clustering of the spatial distributions of the electrostatic potentials was obtained by WebPIPSA (Protein Interaction Property Similarity Analysis; [28], having the use of Hodgkin and Carbo similarity index (SI) [29] (see Methods). The Carbo SI is sensitive to the shape of the potential being considered but not the magnitude, whereas the Hodgkin SI is sensitive to both shape and magnitude. Therefore, WebPIPSA results obtained using the Hodgkin SI are shown in Figures 1, 2, 3, 4 and 5, and evidence from analyses performed using the Carbo SI is cited to confirm parameter independent data.Figure 1

Bottom Line: We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy.Focusing on H5N1, we found that variation at the receptor binding domain surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.In particular, variation in electrostatic and hydropathy patches can provide molecular evolution markers: intriguing surface charge redistribution characterizing the haemagglutinin receptor binding domains from circulating H5N1 clades 2 and 7 might have contributed to antigenic escape hence to their evolutionary success and spreading.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biology and Bioinformatics Unit (MOLBINFO), Department of Biology, University of Padua, via U. Bassi 58/B, 35131, Padova, Italy. irene.righetto@bio.unipd.it.

ABSTRACT

Background: Genome variation is very high in influenza A viruses. However, viral evolution and spreading is strongly influenced by immunogenic features and capacity to bind host cells, depending in turn on the two major capsidic proteins. Therefore, such viruses are classified based on haemagglutinin and neuraminidase types, e.g. H5N1. Current analyses of viral evolution are based on serological and primary sequence comparison; however, comparative structural analysis of capsidic proteins can provide functional insights on surface regions possibly crucial to antigenicity and cell binding.

Results: We performed extensive structural comparison of influenza virus haemagglutinins and of their domains and subregions to investigate type- and/or domain-specific variation. We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy. Focusing on H5N1, we found that variation at the receptor binding domain surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.

Conclusions: Evidence from this work suggests that integrating phylogenetic and serological analyses by extensive structural comparison can help in understanding the 'functional evolution' of viral surface determinants. In particular, variation in electrostatic and hydropathy patches can provide molecular evolution markers: intriguing surface charge redistribution characterizing the haemagglutinin receptor binding domains from circulating H5N1 clades 2 and 7 might have contributed to antigenic escape hence to their evolutionary success and spreading.

Show MeSH
Related in: MedlinePlus