Influenza A Virus Haemagglutinin in Human and Swine: Trends in Molecular Evolution Analyzed via Surface Electrostatic Potential and Normal Modes

The H1N1 influenza A virus caused the 1918 "Spanish flu" pandemic, resulting in 50 to 100 million deaths, with a high mortality rate among young adults. Proposed reasons include bacterial co-infections and a massive host inflammatory response. Influenza viruses are characterized by the haemagglutinin (HA) and neuraminidase (NA) proteins, which determine pathogen-host interactions and transmissibility. HA binds to sialic acid isoforms in the respiratory tract, influencing host specificity, while NA is important for respiratory-droplet spread. Structural analyses of different HA subtypes reveal correlations between surface charge and pathogenicity, though specific markers for highly pathogenic H1N1 strains remain unidentified. In this work, we provide a comparative analysis of H1N1 HA from human and swine hosts. Starting from sequences available on the NCBI Virus database, we collected three different datasets based on the timescale of H1N1: 1918-2008 and 2009-2020 for the human virus, separating the 2009 pandemic H1N1 HA from the previous circulating ones, and 1979-2020 for the swine virus, which is currently circulating. These datasets were then clustered and reduced from thousands to hundreds of sequences for easier analysis. We developed PDB models of the HA receptor binding domain and conducted surface electrostatic potential analyses, due to its importance in binding affinity, and normal modes analyses in order to highlight key regions and residues involved in conformational changes. Our results demonstrated how diverse approaches can be integrated into evolutionary studies to identify trends in viral pathogenicity and interspecies transmissibility.