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Phylogenetic and variability study on all known hemagglutinin subtypes of influenza A virus

Phylogenetic and variability study on all known hemagglutinin subtypes of influenza A virus IntroductionInfluenza A virus is a fairly well-known pathogen that causes the flu. One of the particles found in the influenza virions is the envelope-associated component hemagglutinin (HA). HA is a glycoprotein that plays an important role in the replicative cycle of influenza viruses. The HA consists of three identical monomers that form the cylindrical-shaped structure with the stem domain and globular head domain at the top of the molecule. Also, there is a division into subunits HA1 and HA2. The globular domain contains a fragment of HA1, whereas the stem domain consists of the parts of HA1 and HA2. These two subunits play different functions in the viral replication cycle [1].The first essential function of HA is an attachment of the virus to the surface of the host cell via a sialic acid receptor (N-acetylneuraminic acid). The sialic acid, linked with glycoconjugate, forms the receptor that binds the viral HA [2]. There are two major types of linkage between sialic acid and the carbohydrates: α(2,3) and α(2,6). The α(2,3) sialic acid-linked receptors are recognized by strains of H5N1 (avian influenza). The α(2,6) sialic acid-linked receptors can bind with HAs of human strains. Swine-like strains recognize both types of these receptors [3]. The influenza HA has an affinity with sialic acid receptors via the receptor binding domain (RBD), which is placed in the HA1 subunit. The RBD is located on top of each monomer and has similar configuration in all HA structures. However, the differences in the RBD structures between subtypes cause changes to the affinity of the HA with the hosts’ sialic acid receptors. The RBD is a pocket that consists of three structural elements: 130-loop (from residues 134 to 138), 190-helix (from residues 188 to 190), and 220-loop (from residues 221 to 228) and the other conserved positions (e.g. 98, 153, 183, 193, 194, and 216 in the H1 and H5 strains) [4]. These residues are affected by receptor specificity.The next crucial function of HA is to participate in the fusion of the viral and endosome membrane. Each monomer of HA (called HA0) consists of connected subunits HA1 and HA2 that must be cleaved. The enzymatic cleave of the peptide bond between positions 329 and 330 of the HA0 is realized by the host’s proteases. After the HA0 cleave, there appear two subunits: HA1 has a length of the N-terminus to position 328 and HA2 has a length of position 330 to the C-terminus of the molecule. The amino acid (the most frequent arginine) at position 329 is removed. The newly formed N-terminus of the HA2 subunit is called fusion peptide. This peptide consists of mostly 20–25 of the hydrophobic amino acids that are highly conserved and is hidden inside the molecule at a neutral pH. Under the influence of low pH (value of 5–6) that prevails in endosomes, there is an irreversible change in HA conformation that leads to the fusion of membranes. This allows the release of viral genetic material into the cytoplasm and further into the nucleus where the next stages of the viral life cycle occur [1], [5], [6].Influenza A virus HA is phylogenetically classified into two groups. The first group contains H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16 and the second group contains H3, H4, H7, H10, H14, and H15 [7]. The H17 and H18 subtypes of the virus were recently discovered in bats in Guatemala and Peru [8]. Phylogenetic research suggests that the H17 and H18 subtypes evolved separately in bats over a long period of time [9]. HA is the major antigen of the influenza A virus; therefore, it is the main target for antibodies of the host’s immune system [10]. The high rate of mutation of HA epitopes causes the antibodies obtained at the last contact with the virus to often be ineffective. The organism must again acquire resistance to the virus, and this is one of the reasons for seasonal epidemics.In this paper, we present a comparative research of HA sequences belonging to all currently existing subtypes of influenza A viruses. This study includes phylogenetic analysis by using four different methods, representing the variability profile within all HA subtypes, and finding the consensus sequence. The results have been presented in light of the existing knowledge on the HA of influenza virus type A.Materials and methodsAmino acid sequences of HA and Protein Data Bank (PDB) fileIn this study, we used 160 amino acid sequences belonging to 18 various subtypes of HA. Ten sequences from each subtype have been taken, and except for the H15 strain (eight records have been taken), only one sequence from the H17 strain and one from the H18 strain have been collected. The inadequate number of these strain records is due to the lack of these data in the databases. All sequences used in this work have been obtained from the UniProt Knowledgebase [11]. The HA protein model 2WR0 [12] has been taken from the PDB [13], which is accessible at http://www.rcsb.org. The 2WR0 PDB file (chain A) has been used to show the variability level of certain amino acid residues in the molecule. In the text, the numbering of the amino acids refers to the H3 numbering system, which largely coincides with the numbering of the 2WR0 model (see Figure 3).Bioinformatics softwareThe basis for the analysis performed in this work is the multiple sequence alignment (MSA), which has been constructed using ClustalX [14]. Additionally, this result has been verified with the aid of Kalign [15], T-Coffee [16], Multalin [17], and GEISHA [18] software. The GEISHA program is based on a genetic semihomology algorithm; it is freely available at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/geisha2.jar. The MSAs in some regions were slightly different from each other, so the final MSA was created by manual correction wherever it was necessary. All results shown in this paper are based on the same MSA.The phylogenetic trees have been obtained with the aid of four different applications: ClustalX [14], PHYLIP [19], ConSurf [20], [21], [22], [23], and SSSSg [24]. The algorithm of the SSSSg is based on identity, length, and distribution analysis. The SSSSg program is freely available at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/ssssg/ssssg.zip. This paper presents the four shortened phylogenetic trees constructed based on 18 sequences (each one of them from different subtypes of HA). Full phylogenetic trees have been obtained for all 160 sequences and have been shown in the Supplemental Materials section. The records used to create shortened phylograms have been marked by red dots. The visualizations of phylogenetic trees have been carried out using an NJ plot [25].The ConSurf Server has been used to calculate the profile of variability, which has been plotted on the 2WR0 protein structure and its sequence (see Figure 2).The Chimera software [26] has been used to visualize the 2WR0 protein structure. The Consensus Constructor program [27] has been used to determine the consensus sequence, which is roughly an averaged sequence of all 18 influenza A subtypes. This program can be obtained with no charge at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/ConsConstr.zip.In this study, the results have been obtained using the programs at the default parameters, except for Consensus Constructor whose parameters have been adjusted. The parameters of Consensus Constructor used in the calculation are gaps 50% (80), identity 65% (104), and significance 17.5% (28).Accessibility of original applications created by authors and coworkersThe Consensus Constructor, SSSSg, and GEISHA programs used in this work are freely available at the addresses given in Materials and methods. Also, these applications may be sent directly upon request to the person concerned with using them. The authors will provide technical support if problems using these programs occur.Results and discussionPhylogenetic analysisPhylogenetic analysis has been performed using four different applications. This approach allows one to make the comparison between created trees. For better clarity, the four short trees have been obtained based on 18 HA sequences (each from different subtypes; see Figure 1).Figure 1:Four phylogenetic trees constructed on the basis of the 18 HA sequences.Each sequence belongs to another HA subtype of influenza. The phylograms have been created with the aid of the different programs: (A) Clustal, (B) SSSSg, (C) PHYLIP (maximum likelihood method), and (D) ConSurf. Full phylogenetic trees consisting of 160 sequences are available in the Supplemental Materials section.Within all phylogenetic trees, the clear division into separate clades that contain HA sequences from the same subtype can be seen. However, the SSSSg program presents a slightly different result; the full SSSSg tree does not focus all H2 and H5 sequences in the single clades. Considering the evolutionary relationship between HA strains, Clustal, PHYLIP, and ConSurf programs provided very similar results. On first sight, these trees differ from each other in terms of the distribution of clades. However, the rotation of some clades can show that these results are generally the same and that the main differences are within the length of the branches. A slightly different tree has been presented by SSSSg; this program shows the phylogram with different topologies of some records and clades. By comparing the short to the full trees, it can be see that the Clustal and ConSurf shortened trees present the same relations between strains as full trees. The short PHYLIP tree shows a slightly different position of the H17 and H18 strains in relation to the H2, H5, H1, and H6 strains. The short SSSSg phylogram differs significantly from the full tree.The closest evolutionary relationships that can be observed in each tree are for the H7, H15, and H10 as well as for the H4, H14, and H3 strains. These six subtypes form two closely related clades in each phylogram. The full SSSSg tree also includes the H8 strains within these two clades. The Clustal, PHYLIP, and ConSurf trees show the common origin of the H8, H12, and H9 as well as H13, H16, and H11 subtypes. These six strains form two closely related groups as well. The SSSSg result in terms of these strains is not univocal. The full trees exhibit that the H2, H5, H1, and H6 strains are akin and are also arranged in one clade. These four strains are evolutionarily closest to the recently reported H17 and H18 strains. In this case, the SSSSg program presents a somewhat different result. All four trees show division into two distinct phylogenetic groups, which is consistent with the existing information [7]. However, the full SSSSg tree includes H8 strains (group 1) within the subtypes of group 2.In summary, the phylogenetic trees obtained using Clustal, PHYLIP, and ConSurf show very similar results and should be considered highly reliable. However, the SSSSg presents ambiguous results; some parts of the SSSSg phylograms are in accordance with other trees, but some parts do not fit, so they are less certain. The evolutionary relationships between all strains used in this study adequately illustrate the full phylogenetic trees that are available in the Supplemental Materials section.Variability profile and consensus sequenceThis paper presents the profile of variability obtained using the ConSurf program and the consensus sequence generated with the aid of Consensus Constructor. The mutational variability profile of influenza HA proteins at the level of type A has been placed in Figure 2. The variations of the amino acid residues have been shown on both the 2WR0 protein structure and its sequence.Figure 2:The profile of variability generated for HA sequences belonging to 18 subtypes of influenza.The results have been plotted into chain A of the 2WR0 protein structure and its sequence. The HA model has been shown from three different perspectives. The spatial orientations of the protein structure are represented by small thumbnails with homotrimers; the A chains are highlighted in green. Only selected residues have been indicated on the molecule. The sequence numbering is true for the 2WR0 protein model. The sequence has been presented in relation to the MSA used in this study. The results have been obtained with the aid of ConSurf.The HA protein model has been presented in a native form from three different orientations. There are two major parts of the molecule that have different levels of conservation. These two regions correspond to the HA1 and HA2 subunits. Each monomer of HA consists of HA1 (from the N-terminus to position 328) and HA2 (from position 330 to the C-terminus of the molecule) [1]. In our study, the HA1 subunit is generally characterized by the high variability of amino acids. The HA2 subunit consists of mostly well-conserved residues. Within these subunits are few important regions. One of them is the cleavage site, which is a short motif that contains several amino acids. The cleave of the peptide bond between positions 329 and 330 is realized by the host’s proteases; thereby, the divided HA1 and HA2 subunits appear. The cleavage site is a variable region between various strains. In our study, this site is characterized by many insertions and single mutations between different subtypes. The mutations within this site may have an impact on the pathogenicity of influenza A viruses [28], [29]. After cleavage, the HA2 has the new N-terminus that consists of mostly hydrophobic residues, and it is known as the fusion peptide. This 23 amino acid fragment is crucial to the viral life cycle, and it is responsible for merging the viral and host cell membranes. In terms of fusion peptide, this work presents the strongly conserved residues within all compared strains. However, the positions 344, 346, and 347 are characterized by an average level of conservation; this is consistent with the existing information [30]. Our comparison indicates the additional residues that are not fully conserved: 330, 331, 333, 342, 343, 348, 350, 352, and 353. However, this is due to the occurrence of single mutations in these positions, and this does not change the fact that the whole fusion peptide is strongly conserved in all analyzed strains. Additionally, we checked the residues that form the RBD, which is the site of interaction between HA and the sialic acid. The RBD consists of some of the conserved positions and three elements of the secondary structure: 130-loop, 190-helix, and 220-loop. In our study, most of the residues that form these structural elements are characterized by an average or low level of conservation. Some studies describe a slight difference in residues that form RBD. We checked the positions 98, 153, 183, 193, 194, and 216 that are conserved in the H1 and H5 serotypes [4]. In our research, these residues are conserved, except positions 193 and 216, which are highly variable.Consensus Constructor provides an additional source of information regarding the variation of residues within the investigated set of data. The obtained consensus sequence is a kind of summary of the whole group of sequences studied here.The particular residues of the consensus sequence are occupied by amino acids that occur most frequently in the aligned group of sequences. The consensus and 2WR0 sequences have been presented in Figure 3. The parameters of Consensus Constructor have been determined to minimize the residue number indicated as “X”. The “X” signifies highly variable positions that are occupied by different amino acids in various strains. Residues are marked black to signify the low variable positions that generally correspond to conserved residues indicated by ConSurf. The second sequence (2WR0) has positions marked with a gray color, which means the average level of variability. Comparing the consensus and 2WR0 sequences can reveal many positions that are occupied by the same amino acids, although these have average or variable level of conservation. This indicates a greater similarity of the H2 strain to the whole HA group than other strains in terms of these positions. However, there are many differences between these two sequences as well.Figure 3:The consensus sequence generated with the aid of the Consensus Constructor program and the sequence of the 2WR0 protein structure.The red-colored numbers refer to the H3 numbering system. The black numbering is true for the 2WR0 PDB file. The black-marked residues are the most conservative. For more information, see the text. Consensus Constructor parameters used in the calculation: gaps: 50% (80), identity: 65% (104), significance: 17.5% (28).In summary, this work shows the variability of residues within all known HA strains belonging to influenza virus type A. Many positions that are strongly conserved in one or several subtypes, at the level of type, are average or even variable. The consensus sequence presented here can be used to search related sequences in BLAST and evaluate their relationship [31]. The consensus sequence in FASTA format without gaps is available in the Supplemental Materials section.Author contributions: The authors accept responsibility for the entire content of this article and approved its submission.Research funding: None declared.Employment or leadership: None declared.Honorarium: None declared.Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.References1.Sriwilaijaroen N, Suzuki Y. Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proc Jpn Acad Ser B Phys Biol Sci 2012;88:226–49.2272843910.2183/pjab.88.226SriwilaijaroenNSuzukiYMolecular basis of the structure and function of H1 hemagglutinin of influenza virusProc Jpn Acad Ser B Phys Biol Sci201288226492.Varghese JN, Laver WG, Colman PM. 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Nucleic Acids Res 1997;25: 3389–402.925469410.1093/nar/25.17.3389AltschulSFMaddenTLSchäfferAAZhangJZhangZMillerWGapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Res1997253389402Supplemental Material:The online version of this article (DOI: https://doi.org/10.1515/bams-2017-0009) offers supplementary material, available to authorized users. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bio-Algorithms and Med-Systems de Gruyter

Phylogenetic and variability study on all known hemagglutinin subtypes of influenza A virus

Bio-Algorithms and Med-Systems , Volume 13 (3): 7 – Sep 26, 2017

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10.1515/bams-2017-0009
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Abstract

IntroductionInfluenza A virus is a fairly well-known pathogen that causes the flu. One of the particles found in the influenza virions is the envelope-associated component hemagglutinin (HA). HA is a glycoprotein that plays an important role in the replicative cycle of influenza viruses. The HA consists of three identical monomers that form the cylindrical-shaped structure with the stem domain and globular head domain at the top of the molecule. Also, there is a division into subunits HA1 and HA2. The globular domain contains a fragment of HA1, whereas the stem domain consists of the parts of HA1 and HA2. These two subunits play different functions in the viral replication cycle [1].The first essential function of HA is an attachment of the virus to the surface of the host cell via a sialic acid receptor (N-acetylneuraminic acid). The sialic acid, linked with glycoconjugate, forms the receptor that binds the viral HA [2]. There are two major types of linkage between sialic acid and the carbohydrates: α(2,3) and α(2,6). The α(2,3) sialic acid-linked receptors are recognized by strains of H5N1 (avian influenza). The α(2,6) sialic acid-linked receptors can bind with HAs of human strains. Swine-like strains recognize both types of these receptors [3]. The influenza HA has an affinity with sialic acid receptors via the receptor binding domain (RBD), which is placed in the HA1 subunit. The RBD is located on top of each monomer and has similar configuration in all HA structures. However, the differences in the RBD structures between subtypes cause changes to the affinity of the HA with the hosts’ sialic acid receptors. The RBD is a pocket that consists of three structural elements: 130-loop (from residues 134 to 138), 190-helix (from residues 188 to 190), and 220-loop (from residues 221 to 228) and the other conserved positions (e.g. 98, 153, 183, 193, 194, and 216 in the H1 and H5 strains) [4]. These residues are affected by receptor specificity.The next crucial function of HA is to participate in the fusion of the viral and endosome membrane. Each monomer of HA (called HA0) consists of connected subunits HA1 and HA2 that must be cleaved. The enzymatic cleave of the peptide bond between positions 329 and 330 of the HA0 is realized by the host’s proteases. After the HA0 cleave, there appear two subunits: HA1 has a length of the N-terminus to position 328 and HA2 has a length of position 330 to the C-terminus of the molecule. The amino acid (the most frequent arginine) at position 329 is removed. The newly formed N-terminus of the HA2 subunit is called fusion peptide. This peptide consists of mostly 20–25 of the hydrophobic amino acids that are highly conserved and is hidden inside the molecule at a neutral pH. Under the influence of low pH (value of 5–6) that prevails in endosomes, there is an irreversible change in HA conformation that leads to the fusion of membranes. This allows the release of viral genetic material into the cytoplasm and further into the nucleus where the next stages of the viral life cycle occur [1], [5], [6].Influenza A virus HA is phylogenetically classified into two groups. The first group contains H1, H2, H5, H6, H8, H9, H11, H12, H13, and H16 and the second group contains H3, H4, H7, H10, H14, and H15 [7]. The H17 and H18 subtypes of the virus were recently discovered in bats in Guatemala and Peru [8]. Phylogenetic research suggests that the H17 and H18 subtypes evolved separately in bats over a long period of time [9]. HA is the major antigen of the influenza A virus; therefore, it is the main target for antibodies of the host’s immune system [10]. The high rate of mutation of HA epitopes causes the antibodies obtained at the last contact with the virus to often be ineffective. The organism must again acquire resistance to the virus, and this is one of the reasons for seasonal epidemics.In this paper, we present a comparative research of HA sequences belonging to all currently existing subtypes of influenza A viruses. This study includes phylogenetic analysis by using four different methods, representing the variability profile within all HA subtypes, and finding the consensus sequence. The results have been presented in light of the existing knowledge on the HA of influenza virus type A.Materials and methodsAmino acid sequences of HA and Protein Data Bank (PDB) fileIn this study, we used 160 amino acid sequences belonging to 18 various subtypes of HA. Ten sequences from each subtype have been taken, and except for the H15 strain (eight records have been taken), only one sequence from the H17 strain and one from the H18 strain have been collected. The inadequate number of these strain records is due to the lack of these data in the databases. All sequences used in this work have been obtained from the UniProt Knowledgebase [11]. The HA protein model 2WR0 [12] has been taken from the PDB [13], which is accessible at http://www.rcsb.org. The 2WR0 PDB file (chain A) has been used to show the variability level of certain amino acid residues in the molecule. In the text, the numbering of the amino acids refers to the H3 numbering system, which largely coincides with the numbering of the 2WR0 model (see Figure 3).Bioinformatics softwareThe basis for the analysis performed in this work is the multiple sequence alignment (MSA), which has been constructed using ClustalX [14]. Additionally, this result has been verified with the aid of Kalign [15], T-Coffee [16], Multalin [17], and GEISHA [18] software. The GEISHA program is based on a genetic semihomology algorithm; it is freely available at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/geisha2.jar. The MSAs in some regions were slightly different from each other, so the final MSA was created by manual correction wherever it was necessary. All results shown in this paper are based on the same MSA.The phylogenetic trees have been obtained with the aid of four different applications: ClustalX [14], PHYLIP [19], ConSurf [20], [21], [22], [23], and SSSSg [24]. The algorithm of the SSSSg is based on identity, length, and distribution analysis. The SSSSg program is freely available at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/ssssg/ssssg.zip. This paper presents the four shortened phylogenetic trees constructed based on 18 sequences (each one of them from different subtypes of HA). Full phylogenetic trees have been obtained for all 160 sequences and have been shown in the Supplemental Materials section. The records used to create shortened phylograms have been marked by red dots. The visualizations of phylogenetic trees have been carried out using an NJ plot [25].The ConSurf Server has been used to calculate the profile of variability, which has been plotted on the 2WR0 protein structure and its sequence (see Figure 2).The Chimera software [26] has been used to visualize the 2WR0 protein structure. The Consensus Constructor program [27] has been used to determine the consensus sequence, which is roughly an averaged sequence of all 18 influenza A subtypes. This program can be obtained with no charge at http://atama.wnb.uz.zgora.pl/∼jleluk/software/wlasne/ConsConstr.zip.In this study, the results have been obtained using the programs at the default parameters, except for Consensus Constructor whose parameters have been adjusted. The parameters of Consensus Constructor used in the calculation are gaps 50% (80), identity 65% (104), and significance 17.5% (28).Accessibility of original applications created by authors and coworkersThe Consensus Constructor, SSSSg, and GEISHA programs used in this work are freely available at the addresses given in Materials and methods. Also, these applications may be sent directly upon request to the person concerned with using them. The authors will provide technical support if problems using these programs occur.Results and discussionPhylogenetic analysisPhylogenetic analysis has been performed using four different applications. This approach allows one to make the comparison between created trees. For better clarity, the four short trees have been obtained based on 18 HA sequences (each from different subtypes; see Figure 1).Figure 1:Four phylogenetic trees constructed on the basis of the 18 HA sequences.Each sequence belongs to another HA subtype of influenza. The phylograms have been created with the aid of the different programs: (A) Clustal, (B) SSSSg, (C) PHYLIP (maximum likelihood method), and (D) ConSurf. Full phylogenetic trees consisting of 160 sequences are available in the Supplemental Materials section.Within all phylogenetic trees, the clear division into separate clades that contain HA sequences from the same subtype can be seen. However, the SSSSg program presents a slightly different result; the full SSSSg tree does not focus all H2 and H5 sequences in the single clades. Considering the evolutionary relationship between HA strains, Clustal, PHYLIP, and ConSurf programs provided very similar results. On first sight, these trees differ from each other in terms of the distribution of clades. However, the rotation of some clades can show that these results are generally the same and that the main differences are within the length of the branches. A slightly different tree has been presented by SSSSg; this program shows the phylogram with different topologies of some records and clades. By comparing the short to the full trees, it can be see that the Clustal and ConSurf shortened trees present the same relations between strains as full trees. The short PHYLIP tree shows a slightly different position of the H17 and H18 strains in relation to the H2, H5, H1, and H6 strains. The short SSSSg phylogram differs significantly from the full tree.The closest evolutionary relationships that can be observed in each tree are for the H7, H15, and H10 as well as for the H4, H14, and H3 strains. These six subtypes form two closely related clades in each phylogram. The full SSSSg tree also includes the H8 strains within these two clades. The Clustal, PHYLIP, and ConSurf trees show the common origin of the H8, H12, and H9 as well as H13, H16, and H11 subtypes. These six strains form two closely related groups as well. The SSSSg result in terms of these strains is not univocal. The full trees exhibit that the H2, H5, H1, and H6 strains are akin and are also arranged in one clade. These four strains are evolutionarily closest to the recently reported H17 and H18 strains. In this case, the SSSSg program presents a somewhat different result. All four trees show division into two distinct phylogenetic groups, which is consistent with the existing information [7]. However, the full SSSSg tree includes H8 strains (group 1) within the subtypes of group 2.In summary, the phylogenetic trees obtained using Clustal, PHYLIP, and ConSurf show very similar results and should be considered highly reliable. However, the SSSSg presents ambiguous results; some parts of the SSSSg phylograms are in accordance with other trees, but some parts do not fit, so they are less certain. The evolutionary relationships between all strains used in this study adequately illustrate the full phylogenetic trees that are available in the Supplemental Materials section.Variability profile and consensus sequenceThis paper presents the profile of variability obtained using the ConSurf program and the consensus sequence generated with the aid of Consensus Constructor. The mutational variability profile of influenza HA proteins at the level of type A has been placed in Figure 2. The variations of the amino acid residues have been shown on both the 2WR0 protein structure and its sequence.Figure 2:The profile of variability generated for HA sequences belonging to 18 subtypes of influenza.The results have been plotted into chain A of the 2WR0 protein structure and its sequence. The HA model has been shown from three different perspectives. The spatial orientations of the protein structure are represented by small thumbnails with homotrimers; the A chains are highlighted in green. Only selected residues have been indicated on the molecule. The sequence numbering is true for the 2WR0 protein model. The sequence has been presented in relation to the MSA used in this study. The results have been obtained with the aid of ConSurf.The HA protein model has been presented in a native form from three different orientations. There are two major parts of the molecule that have different levels of conservation. These two regions correspond to the HA1 and HA2 subunits. Each monomer of HA consists of HA1 (from the N-terminus to position 328) and HA2 (from position 330 to the C-terminus of the molecule) [1]. In our study, the HA1 subunit is generally characterized by the high variability of amino acids. The HA2 subunit consists of mostly well-conserved residues. Within these subunits are few important regions. One of them is the cleavage site, which is a short motif that contains several amino acids. The cleave of the peptide bond between positions 329 and 330 is realized by the host’s proteases; thereby, the divided HA1 and HA2 subunits appear. The cleavage site is a variable region between various strains. In our study, this site is characterized by many insertions and single mutations between different subtypes. The mutations within this site may have an impact on the pathogenicity of influenza A viruses [28], [29]. After cleavage, the HA2 has the new N-terminus that consists of mostly hydrophobic residues, and it is known as the fusion peptide. This 23 amino acid fragment is crucial to the viral life cycle, and it is responsible for merging the viral and host cell membranes. In terms of fusion peptide, this work presents the strongly conserved residues within all compared strains. However, the positions 344, 346, and 347 are characterized by an average level of conservation; this is consistent with the existing information [30]. Our comparison indicates the additional residues that are not fully conserved: 330, 331, 333, 342, 343, 348, 350, 352, and 353. However, this is due to the occurrence of single mutations in these positions, and this does not change the fact that the whole fusion peptide is strongly conserved in all analyzed strains. Additionally, we checked the residues that form the RBD, which is the site of interaction between HA and the sialic acid. The RBD consists of some of the conserved positions and three elements of the secondary structure: 130-loop, 190-helix, and 220-loop. In our study, most of the residues that form these structural elements are characterized by an average or low level of conservation. Some studies describe a slight difference in residues that form RBD. We checked the positions 98, 153, 183, 193, 194, and 216 that are conserved in the H1 and H5 serotypes [4]. In our research, these residues are conserved, except positions 193 and 216, which are highly variable.Consensus Constructor provides an additional source of information regarding the variation of residues within the investigated set of data. The obtained consensus sequence is a kind of summary of the whole group of sequences studied here.The particular residues of the consensus sequence are occupied by amino acids that occur most frequently in the aligned group of sequences. The consensus and 2WR0 sequences have been presented in Figure 3. The parameters of Consensus Constructor have been determined to minimize the residue number indicated as “X”. The “X” signifies highly variable positions that are occupied by different amino acids in various strains. Residues are marked black to signify the low variable positions that generally correspond to conserved residues indicated by ConSurf. The second sequence (2WR0) has positions marked with a gray color, which means the average level of variability. Comparing the consensus and 2WR0 sequences can reveal many positions that are occupied by the same amino acids, although these have average or variable level of conservation. This indicates a greater similarity of the H2 strain to the whole HA group than other strains in terms of these positions. However, there are many differences between these two sequences as well.Figure 3:The consensus sequence generated with the aid of the Consensus Constructor program and the sequence of the 2WR0 protein structure.The red-colored numbers refer to the H3 numbering system. The black numbering is true for the 2WR0 PDB file. The black-marked residues are the most conservative. For more information, see the text. Consensus Constructor parameters used in the calculation: gaps: 50% (80), identity: 65% (104), significance: 17.5% (28).In summary, this work shows the variability of residues within all known HA strains belonging to influenza virus type A. Many positions that are strongly conserved in one or several subtypes, at the level of type, are average or even variable. The consensus sequence presented here can be used to search related sequences in BLAST and evaluate their relationship [31]. 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Bio-Algorithms and Med-Systemsde Gruyter

Published: Sep 26, 2017

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