  Influenza virus contains two highly variable envelope glycoproteins,
hemagglutinin (HA) and neuraminidase (NA). The structure and properties of HA,
which is responsible for binding the virus to the cell that is being infected,
change significantly when the virus is transmitted from avian or swine species
to humans. Previously we identified much smaller human individual evolutionary
amino acid mutational changes in NA, which cleaves sialic acid groups and is
required for influenza virus replication. We showed that these smaller changes
can be monitored very accurately across many Uniprot and NCBI strains using
hydropathicity scales to quantify the roughness of water film packages, which
increases gradually due to migration, but decreases abruptly under large-scale
vaccination pressures. Here we show that, while HA evolution is much more
complex, it still shows abrupt punctuation changes linked to those of NA. HA
exhibits proteinquakes, which resemble earthquakes and are related to
hydropathic shifting of sialic acid binding regions. HA proteinquakes based on
sialic acid interactions are required for optimal balance between the
receptor-binding and receptor-destroying activities of HA and NA for efficient
virus replication. Our comprehensive results present an historical (1945-2011)
panorama of HA evolution over thousands of strains, and are consistent with
many studies of HA and NA interactions based on a few mutations of a few
strains. While the common influenza virus discussed here has been rendered
almost harmless by decades of vaccination programs, the sequential decoding
lessons learned here are applicable to other viruses that are emerging as
powerful weapons for controlling and even curing common organ cancers. Those
engineered oncolytic drugs will be discussed in future papers.
