Research Article Proteinquakes in the Evolution of Influenza Virus Hemagglutinin (A/H1N1) under Opposing Migration and Vaccination Pressures

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Here we show that, while HA evolution ismuchmore complex thanNA evolution, it still shows abrupt punctuation changes linked to punctuation changes ofNA.HA exhibits proteinquakes, which resemble earthquakes and are related to hydropathic shifting of sialic acid binding regions. HA proteinquakes based on shifting 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 a 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. 1