Dataset Information

Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus.

ABSTRACT: Influenza A has caused several deadly pandemics throughout human history. The virus is often resistant to developed treatments because of its genetic drift or shift property. Broad-spectrum antibodies show a promising potential to overcome the resistance of influenza viruses. In silico studies on broad-reactive antibodies and their interactions with hemagglutinins might shed light on the rational design of a universal vaccine. In this study, 11 broad-spectrum antibodies (or antigen-binding fragments) and 14 hemagglutinins of H3N2 and H5N1 strains were docked and analyzed to provide information about the construction of the scaffold for using universal antibodies against the influenza A virus. Antigen-binding fragments that have high number of appearances in the top 3 within each H3 and H5 subtypes were chosen for protein-protein interaction analysis. The results show that while the hydrogen bond is important for Ab/Fab binding to H3, the H5-Ab/Fab system may need cation-pi interaction for a strong interaction.

SUBMITTER: Le KP

PROVIDER: S-EPMC6747855 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus.

Le Khanh Pb KP Do Phuc-Chau PC Amaro Rommie E RE Le Ly L

Evolutionary bioinformatics online 20190916

Influenza A has caused several deadly pandemics throughout human history. The virus is often resistant to developed treatments because of its genetic drift or shift property. Broad-spectrum antibodies show a promising potential to overcome the resistance of influenza viruses. <i>In silico</i> studies on broad-reactive antibodies and their interactions with hemagglutinins might shed light on the rational design of a universal vaccine. In this study, 11 broad-spectrum antibodies (or antigen-bindin ...[more]

PMID: 31555044

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Project description:In studying the binding of host antibodies to the surface antigens of pathogens, the structural and functional characterization of antibody-antigen complexes by X-ray crystallography and binding assay is important. However, the characterization requires experiments that are typically time consuming and expensive: thus, many antibody-antigen complexes are under-characterized. For vaccine development and disease surveillance, it is often vital to assess the impact of amino acid substitutions on antibody binding. For example, are there antibody substitutions capable of improving binding without a loss of breadth, or antigen substitutions that lead to antigenic escape? The questions cannot be answered reliably from sequence variation alone, exhaustive substitution assays are usually impractical, and alanine scans provide at best an incomplete identification of the critical residue-residue interactions. Here, we show that, given an initial structure of an antibody bound to an antigen, molecular dynamics simulations using the energy method molecular mechanics with Generalized Born surface area (MM/GBSA) can model the impact of single amino acid substitutions on antibody-antigen binding energy. We apply the technique to three broad-spectrum antibodies to influenza A hemagglutinin and examine both previously characterized and novel variant strains observed in the human population that may give rise to antigenic escape. We find that in some cases the impact of a substitution is local, while in others it causes a reorientation of the antibody with wide-ranging impact on residue-residue interactions: this explains, in part, why the change in chemical properties of a residue can be, on its own, a poor predictor of overall change in binding energy. Our estimates are in good agreement with experimental results-indeed, they approximate the degree of agreement between different experimental techniques. Simulations were performed on commodity computer hardware; hence, this approach has the potential to be widely adopted by those undertaking infectious disease research. Novel aspects of this research include the application of MM/GBSA to investigate binding between broadly binding antibodies and a viral glycoprotein; the development of an approach for visualizing substrate-ligand interactions; and the use of experimental assay data to rescale our predictions, allowing us to make inferences about absolute, as well as relative, changes in binding energy.

Dataset Information

Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus.

Publications

Molecular Docking of Broad-Spectrum Antibodies on Hemagglutinins of Influenza A Virus.

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