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. 2025 Aug 25;10(35):40416–40421. doi: 10.1021/acsomega.5c05850

Conformational Variability Prediction of H5N1 Avian Influenza A Virus Hemagglutinins with Amino Acid Mutations Using SSSCPreds

Hiroshi Izumi †,*, Laurence A Nafie ‡,§, Rina K Dukor §
PMCID: PMC12423806  PMID: 40949225

Abstract

The worldwide outbreak of the highly pathogenic avian influenza (HPAI) H5N1 virus has sent egg prices soaring. Concomitantly, bovine and human infections of H5N1 viruses have also been observed, but there is no known person-to-person spread. The shape of the motifs is important for receptor recognition of viruses and is contradictorily deformed with amino acid mutations to avoid immunity. The deep neural network-based conformational variability prediction system of protein structures (SSSCPreds) suggests that the outbreak of HPAI is occurring in the avian world, just as the outbreak of SARS-CoV-2 was seen in the human world. The predicted flexible motif with the mutations N236K/Q238L of the B3.13 virus rationally explained the difference of specificity switching by the mutations between B3.13 and wild-type viruses, and the B-factor values were consistent with the prediction by SSSCPreds. Although the difference of only three common amino acid mutations T211I, V226A, and R341K near the sialic acid-dependent pathway and the furin cleavage sites exists between B3.13 and D1.1 viruses, the mutations of Q338L/R341K, which show the predicted rigid map pattern of the C-terminus, are one of the remarkable factors for the large difference of the case numbers for the bovine and human infections between B3.13 and D1.1 viruses.

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Introduction

Highly pathogenic avian influenza (HPAI) H5N1 virus has led to frequent outbreaks in poultry farms and resulted in millions of deaths among chickens, ducks, and geese. The worldwide outbreak since early 2024 has sent not only egg prices soaring but also bovine and human infections in the United States. At the moment, there is no known person-to-person spread. The potential of a 33-amino acid long peptide containing multiple basic amino acids RERRRKKR at the furin cleavage site to penetrate various cells and lung tissue through a sialic acid-independent endocytotic pathway has been reported. Further, neuropilin-1 (NRP1) is another host factor related to the multiple basic amino acid sequences at the furin cleavage site that facilitates SARS-CoV-2 infection , and has been identified as a direct cargo sorted by the endosomal SNX-BAR sorting complex promoting exit 1 (ESCPE-1) for the endosomal sorting related to the retrograde transport from endosomes to the trans-Golgi network. The concerned H5N1 genotypes B3.13 and D1.1, which belong to clade 2.3.4.4b, have a Q338L mutation near the furin cleavage site, and an R341K mutation is seen in the B3.13 virus further.

Receptors for host cell entry recognize motifs of membrane-fusion proteins on the surfaces of viruses and are very sensitive to the shapes of the motifs. Even though there are identical amino acid sequences of viruses, it sometimes happens that the motifs with the different conformations depending on the sequence length cannot be recognized. For example, for the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp160 precursor, it has been reported that even though short gp160 peptides are efficiently cleaved in vitro by furin at Arg511, the full length gp160 was shown not to be efficiently cleaved ex vivo. As for the short C-end rule (CendR) peptides of SARS-CoV-2 Omicron, Delta, and Alpha variants, the difference of interactions depending on the sequence lengths has also been observed.

The deep neural network-based conformational variability prediction system of protein structures (SSSCPreds) using supersecondary structure code (SSSC), which has been approved as a protocol in a molecular biology database, shows a high level of prediction accuracy , and can be used to detect an uncompetitive inhibition mechanism related to the drug resistance of Candida auris FKS1 by amino acid mutations. In this article, we validate the impact of the amino acid mutations near the sialic acid-dependent endocytotic pathway and the furin cleavage sites between H5N1 genotypes B3.13, D1.1, and wild-type (A/Vietnam/1203/2004) viruses.

Results and Discussion

Mutation of Sialic Acid-Dependent Pathway Site

A large difference of the case numbers for the bovine and human infections between B3.13 and D1.1 viruses has been recorded. The difference in only three common amino acid mutations T211I, V226A, and R341K near the sialic acid-dependent pathway and the furin cleavage sites exists between these viruses. The wild-type virus also has T211, V226, and R341 but not the mutation Q338L observed in both B3.13 and D1.1. Further, the mutations Q338L and R341K are detected in the human case of England (A/England/0480160/2025), but the mutations T211I and V226A are not observed. These observations strongly suggest that the mutations Q338L and R341K are correlated to the recent outbreaks. To validate the impact of the amino acid mutations, the conformational variability prediction of B3.13, D1.1, and wild-type viruses using SSSCPreds was carried out.

The predicted flexibility/rigidity maps near the sialic acid-dependent pathway site well reproduced those of the protein data bank (PDB) data of B3.13 (9DIP, 9DIQ, and 9DIO), wild type (2FK0), and H1N1pdm (3M6S) viruses including the structured loops (Figure ). The concordance rates between the observed and predicted SSSCs for the entire motifs were as follows: 9DIP_A: 0.938–0.913; 9DIQ_A: 0.932–0.914; 9DIO_A: 0.923–0.885; 2FK0_A; 0.926–0.913; and 3M6S_A: 0.942–0.933. Recently, it has been reported that the mutations Q238L and N236K/Q238L of B3.13 virus switch specificity from avian to human receptors. However, the mutations N170D/N236K/Q238L/T331I of wild type virus are transmissible in ferrets but only the mutations N236K/Q238L are not. The mutation N170D of wild type virus results in loss of a glycosylation site, but N170 remains in the B3.13 virus.

1.

1

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Sequence flexibility/rigidity maps of B3.13, D1.1, wild-type, and H1N1pdm viruses near the sialic acid-dependent pathway site with experimental SSSC maps (green: flexible conformation; red: α-helix-type conformation; yellow: β-sheet-type conformation; blue: other-type conformations; and black frame: mutation site).

The backbone conformations of motifs for B3.13 virus (9DIP), B3.13 virus with the mutation Q238L (9DIO), and the wild type (2FK0) near the sialic acid-dependent pathway site very resemble each other (Figure ). The switching specificity motif by the mutation Q238L (9DIP, 9DIQ, 9DIO, 2FK0, and 3M6S) can be represented as the SSSC sequence SSSSSTTSHSSSSS (H: α-helix-type conformation; S: β-sheet-type conformation; and T: other-type conformations), converted by using SSSCview, and is a relatively rare one in the 582,665 FASTA-format files of protein subunits containing the amino acid and SSSC sequences (Table S1). This motif of nitrous-oxide reductase (1QNI) interacts with a (μ-4-sulfido)-tetra-nuclear copper ion, and both the switching specificity motifs with and without the mutation Q238L (9DIP and 9DIO) also contact the sialic acid (Figure ). The predicted flexibility/rigidity maps of B3.13 and wild-type viruses explain these phenomena. Although the mutations Q238L and N236K/Q238L of B3.13 virus largely increased the variability of the site, the map pattern of the mutations N236K/Q238L for the wild-type virus was unchanged (Figure ), and then the shape of backbone conformation was deformed by the mutation N170D (Figure ). B3.13 virus exhibits strong binding to α2–3 sialosides SLN3, with an apparent dissociation constant (K D) of 138 nM, whereas no binding to α2–6 SLN3 was detected (K D > 1 mM). The binding specificity was completely switched from avian-type to human-type receptors by the mutation Q238L (K D = 23 μM), with no detectable binding to α2–3 sialosides (K D > 1 mM). The predicted conformational variability result supports this switching, and the B-factor values (Figure ), which indicate the relative vibrational motion of different parts of the structure, are consistent with the predictions by SSSCPreds. Further, most of the mutations detected in the severe human cases of Louisiana and British Columbia showed a broad range of the predicted conformational flexibility. Although the person-to-person spread has not been reported now, the prediction results suggest the reassembly of conformational architectures, so it is necessary to trace the trends of mutations. The predicted flexibility/rigidity maps of H1N1pdm viruses near the sialic acid-dependent pathway site can be utilized as the reference for the person-to-person spread because the conformational variability patterns of hemagglutinins for human influenza A H1N1pdm viruses extremely resemble those for avian H5N1 viruses, except for the furin cleavage site. In any case, mutations T211I and V226A do not have a very large impact on the case numbers for bovine and human infections in view of the transmissible virus references and the predicted conformational variability.

2.

2

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Conformational variability maps (green: variable conformation; red: α-helix-type conformation; yellow: β-sheet-type conformation; and blue: other-type conformations) of the sialic acid-dependent pathway site (LSTa: Neu5Acα2–3Galβ1–3GlcNAcβ1–3Galβ1–4Glc; LSTc: Neu5Acα2–6Galβ1–4GlcNAcβ1–3Galβ1–4Glc; SIA: sialic acid; GAL: D-galactose; NAG: N-acetyl-β-d-glucosamine; and BMA: D-mannose) for B3.13 virus on PDB ID 9DIP (A) with B-factor values (blue: low; red: high) on PDB ID 9DIP (B), B3.13 virus with mutation Q238L on PDB ID 9DIO (C), with B-factor values (blue: low; red: high) on PDB ID 9DIO (D), wild type virus on PDB ID 2FK0 (E), and wild type virus with mutations N236K/Q238L on PDB ID 2FK0 (F).

Mutation of Furin Cleavage Site

The conformational change with the predicted largely flexible SSSC sequences correlates well with the neutralization escape ability and the drug resistance. − The predicted flexibility/rigidity maps near the furin cleavage site also reproduced those of the PDB data of B3.13 (9DIP and 9DIO) and wild type (2FK0) viruses, except the invisible furin cleavage site itself (Figure and Figure S1). The mutations N170D/N236K/Q238L/T331I of the wild-type virus mentioned above did not affect the predicted conformational variability of the C-terminus at the furin cleavage site. On the other hand, the conformational variability map patterns of the C-termini of B3.13, D1.1, and wild-type viruses were largely different, and it is similar to the consequence of Alpha, Delta, and Omicron variants for SARS-CoV-2. The map patterns rationalize the worldwide outbreaks since 2021.

3.

3

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Sequence flexibility/rigidity maps of H5N1 viruses near the furin cleavage site with experimental SSSC maps (green: flexible conformation; red: α-helix-type conformation; yellow: β-sheet-type conformation; blue: other-type conformations; and black frame: mutation site).

Only the mutation Q338L observed in both B3.13 and D1.1 made the map pattern of the C-terminus extremely flexible. The H9N2 virus (A/chicken/Japan/AQ–HE31–26/2020) was dominant in Japan before 2021. The mutation Q338L with mutations near the sialic acid-dependent pathway site is one of the factors of the outbreak, as well as mutations near the furin cleavage site and at the receptor binding domain for SARS-CoV-2. Then, the R341K mutation largely changed the map pattern of the C-terminus to rigid. Furthermore, the S336N mutation for the B3.13 virus in California has been observed, but the map pattern of the C-terminus remains rigid. The rigid pattern correlates with the high infectivity of the B3.13 virus because the receptor recognizes the shape of the motifs. On the other hand, it is suggested that the rigid motifs allow immunity to work quickly, which lead to low pathogenicity, and the B3.13 virus in California has evolved to deal with trade-offs. The correlation among mutation, phenotype, and predicted conformational variability is summarized in Table . More recently, further mutations near the furin cleavage site have been observed (A/CATTLE/USA/25–000586–013/2025 and A/Cattle/USA/24–034196–001/2024). These mutations have the possibility of new outbreaks; therefore, a trend survey is necessary.

1. Correlation among Mutation, Phenotype, and Predicted Conformational Variability.

mutation phenotype predicted conformational variability
Q238L (B3.13) switching specificity variable
N236K/Q238L (B3.13) switching specificity variable
N236K/Q238L (Wild type) no switching specificity rigid
Q338L (D1.1) high pathogenicity variable (C-terminus)
Q338L/R341K (B3.13) low pathogenicity rigid (C-terminus)
S336N/Q338L/R341K (B3.13) low pathogenicity rigid (C-terminus)
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Conclusions

In conclusion, SSSCPreds reproduced well the difference of specificity switching by the mutations N236K/Q238L between B3.13 and wild-type viruses. In view of the predicted conformational variability and the transmissible virus references, the effect of the mutations T211I and V226A on the case numbers for bovine and human infections is not very large. The predicted map pattern changes of the C-termini for B3.13, D1.1, and wild-type viruses resembled those for Alpha, Delta, and Omicron variants of SARS-CoV-2. The rigid map patterns by the mutations of Q338L/R341K suggest a correlation with the high infectivity and low pathogenicity of the B3.13 virus.

Computational Methods

SSSCview ,

Conformational elements show classification of dihedral angles, and the elements 1, 2, 3, 4, 5, and 6 correspond to conformational terms ap (antiperiplanar), + sc (+synclinal), – sc (−synclinal), sp (synperiplanar), + ac (+anticlinal), and – ac (−anticlinal), respectively. , The terms, c and a, in the conformational elements correspond to clockwise and anticlockwise, respectively. , The conformational elements at each angle location were gained using PDB data of protein molecules according to the classification. SSSC was indicated as a conformation term for each amino acid backbone unit using the letters H, S, T, and D referring to an α-helix-type conformation (H), a β-sheet-type conformation (S), a variety of other-type conformations (T), and disordered residues or the C-terminus (D), which was derived from the template patterns, shown as conformational codes, such as 3a5c4a (α-helix-type conformation) and 6c4a4a (β-sheet-type conformation). ,

The autoconversion conformation information needed for SSSC was conducted by the following procedures: (1) extraction process of four atomic coordinates for determination of dihedral angles from PDB data, (2) conversion process from dihedral angles to conformational codes, and (3) strict and/or fuzzy search processes of structural code homology. , In the fuzzy search of structural code homology (process 3), it was calculated that the homology was high if the conformational elements were included in the range of 90°. Specifically, there were 12 sets, {4c, 2a, 2c}, {2a, 2c, 5a}, {2c, 5a, 5c}, {5a, 5c, 1a}, {5c, 1a, 1c}, {1a, 1c, 6a}, {1c, 6a, 6c}, {6a, 6c, 3a}, {6c, 3a, 3c}, {3a, 3c, 4a}, {3c, 4a, 4c}, and {4a, 4c, 2a}, in the range of 90°. It was supposed that a set of these sets was X = {p, q, r}, and a conformational element, which was compared at a specific angle location, was y. If all elements fulfilled the equation, y ∈ X, it was calculated that the structural code homology of the angle location was high. , Finally, the structural code homology of the main chain for each amino acid backbone unit was calculated as the logical conjunction of structural code homology at the angle locations. ,

The observed PDB structure files were translated to the FASTA-format files containing the amino acid sequences and SSSCs of protein subunits using SSSCview. , The characterization of other-type conformations (T) in Table S1 was also conducted using SSSCview. ,

SSSCPreds ,

A total of 582,813 FASTA-format files containing the amino acid sequences and SSSCs of protein subunits were gained from 139,932 PDB files by using the SSSCview. , Of these FASTA files, 379,334 files containing subunits with more than or equal to 100 continuous amino acid residues were obtained, and from those files, 150,000 files were obtained as training data for the deep neural network, 10,000 files were obtained as test data for the deep neural network, and three sets of 10,000 files were obtained as test data for the inference system were randomly selected.

From each FASTA file, a set of 100 continuous amino acid residues and the corresponding SSSC were randomly gained. SSSC terms “H”, “S”, “T”, and “D” were translated to [1,0,0,0], [0,1,0,0], [0,0,1,0], and [0,0,0,1], respectively, and a set of matrices (100, 4) was constructed. The amino acid sequence was also similarly translated.

Deep learning for the prediction of SSSCs from amino acid sequences was carried out by using Neural Network Console 1.40. The revised template of network “12_residual_learning.sdcproj” for the standard MNIST (Modified National Institute of Standards and Technology) data set was applied to provide the initial structure of the deep neural network, which was then trained with our prepared training data set (activation function: ReLU; cost function: HuberLoss; max epoch: 20; batch size: 64; precision: float; structure search: Network Feature + Gaussian Process; updater: Adam; update interval: 1 iteration; alpha: 0.001; beta1: 0.9; beta2: 0.999; epsilon: 1 × 10–8). The 150,000 training data files and the 10,000 test data files for the prediction of SSSCs from amino acid sequences using the deep neural network were also tested to calculate the concordance rate. The gained network and parameters were applied to the SSSCPred inference system, and the system was set to examine amino acid sequences containing at least 100 amino acid residues. For each amino acid sequence, SSSC terms were calculated for every 50 continuous amino acid residues and for the initial and final 100 amino acid residues in the sequence. Then, the first 70 SSSC terms in the sequence were selected followed by every 50 SSSC terms; any remaining SSSC terms at the end of the sequence were also selected. The other prepared three sets of 10,000 test data files for the SSSCPred inference system were then used to calculate concordance rate using agreements of H, S, T, D symbols.

Two additional deep-neural-network-based prediction systems were constructed by using procedures similar to that used to obtain SSSCPred. The three prediction programs for SSSCPreds (SSSCPred200, SSSCPred100 and SSSCPred) were gained as follows. Training data of 200 continuous amino acid residues and 150,000 subunits were used to gain SSSCPred200; those of 100 continuous amino acid residues and 350,000 subunits were used for SSSCPred100; and those of 100 continuous amino acid residues and 150,000 subunits were used for SSSCPred. The conformational variability for each amino acid backbone unit was calculated by using SSSCPreds as the following conformations, a variable conformation (green), an α-helix-type conformation (red), a β-sheet-type conformation (yellow), and a variety of other-type conformations (blue). The sequence variability map was obtained using the Python script with python-docx. The conformational variability map on molecular model was created using the Python script with PyMOL.

The X-ray crystallographic data of H5N1 and H1N1pdm viruses were downloaded from PDBj. The B-factor values were gained from the PDB files. The amino acid sequences of H5N1 and H1N1pdm viruses were gained from UniProt, NCBI (National Center for Biotechnology Information), or Nextstrain. Software SSSCPreds and SSSCview have been deposited on H.I. Web site (https://staff.aist.go.jp/izumi.h/SSSCPreds/index-e.html) and are freely available.

Supplementary Material

ao5c05850_si_001.pdf (486.2KB, pdf)

Acknowledgments

We thank M. Imai and Y. Kawaoka (Department of Virology, Institute of Medical Science, University of Tokyo) for helpful discussions on the mutations N170D/N236K/Q238L/T331I of the wild-type virus. This work was supported by JSPS KAKENHI Grant Numbers JP22K05073,JP25K08630.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c05850.

  • Experimental SSSC map of the furin cleavage site with conformational variability map, main subunits containing motif with SSSC sequence SSSSSTTSHSSSSS, SSSCPreds data of H5N1 genotypes B3.13, D1.1, wild-type (A/Vietnam/1203/2004), and H1N1pdm viruses, and SSSC data of PDB structures (PDF)

H.I. carried out the conceptualization, investigation, and writing of the manuscript and provided the methodology and software. L.A.N. and R.K.D. performed research organization and writing of the manuscript.

The authors declare the following competing financial interest(s): H.I. listed as an inventor on patents US11119033B2 and JP4691728B2 related to software.

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Associated Data

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Supplementary Materials

ao5c05850_si_001.pdf (486.2KB, pdf)

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