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Proteinquakes in the evolution of influenza virus hemagglutinin (A/H1N1) under opposing migration and vaccination pressures.

Phillips JC - Biomed Res Int (2015)

Bottom Line: Here we show that, while HA evolution is much more complex than NA evolution, it still shows abrupt punctuation changes linked to punctuation changes of NA.HA exhibits proteinquakes, which resemble earthquakes and are related to hydropathic shifting of sialic acid binding regions.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Rutgers University, Piscataway, NJ 08854, USA.

ABSTRACT
Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Here we show that, while HA evolution is much more complex than NA evolution, it still shows abrupt punctuation changes linked to punctuation changes of NA. 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.

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Related in: MedlinePlus

North Carolina response to swine flu vaccination program, which began in 2007. The small response in 2008 is greatly enhanced by 2009, after which changes were minimal. The key mutations from 2008 (ACD45795) to 2009 (ADM21399) often involve not individual sites but short strings, for instance, TATY13-16ATAN, LLISKE86-91SLSTAS, and TVT144-147DSNK, indicative of both long-range hydrophilic softening and short-range expansion, including the hydrophilic insertion 144D. The strongly antibody producing epitopes for California 2009 [6] were all at HA1 hydropathic maxima (38–73), (318–332) or minima (158–182). Thus the hydroprofile shown here is more informative than the Euclidean structural illustration shown as an inset to Figure 2 of [6].
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fig10: North Carolina response to swine flu vaccination program, which began in 2007. The small response in 2008 is greatly enhanced by 2009, after which changes were minimal. The key mutations from 2008 (ACD45795) to 2009 (ADM21399) often involve not individual sites but short strings, for instance, TATY13-16ATAN, LLISKE86-91SLSTAS, and TVT144-147DSNK, indicative of both long-range hydrophilic softening and short-range expansion, including the hydrophilic insertion 144D. The strongly antibody producing epitopes for California 2009 [6] were all at HA1 hydropathic maxima (38–73), (318–332) or minima (158–182). Thus the hydroprofile shown here is more informative than the Euclidean structural illustration shown as an inset to Figure 2 of [6].

Mentions: The large value of W, as well as the dominance of overall interactions with sialic acid on the length scale W ~ 111, explains why the details of glycosylation interactions on the length scale of glycosylation spacing (three times smaller) are important only for large-scale strain differences. A survey of 50 immunodominant epitopes (typically 15 aa long) spanning HA Calif 04/2009 revealed a distinct subset that had nearly equal autoantibody interactions almost twice as strong as the remaining epitopes [12]. There are four epitopes in this remarkable subset. As expected, all of these four occurred among the 34 epitopes in the head region below 350. The single criterion that these four (about 10% of all head epitopes studied) satisfied is that they are all either in hydrophobic or hydrophilic extrema (see also Figure 10). The likelihood of such a subset occurring accidentally is <10−7. Note that the strong interactions were equally strong for all four cases. This is what one expects, as the two kinds of extrema are weighted equally in calculating the variance, which does not depend on the sign of the deviation from average. However, the equal weighting is surprising in Euclidean terms, as the hydrophobic/hydrophilic epitopes are on the inside/outside of the globular cluster, and inside/outside are not obviously equivalent. Finally, one of the sites identified as significant by glycan microarray analysis [10] is 190, which is seen in the chain hydroprofiles (Figure 3) as one of several hydrophilic extrema.


Proteinquakes in the evolution of influenza virus hemagglutinin (A/H1N1) under opposing migration and vaccination pressures.

Phillips JC - Biomed Res Int (2015)

North Carolina response to swine flu vaccination program, which began in 2007. The small response in 2008 is greatly enhanced by 2009, after which changes were minimal. The key mutations from 2008 (ACD45795) to 2009 (ADM21399) often involve not individual sites but short strings, for instance, TATY13-16ATAN, LLISKE86-91SLSTAS, and TVT144-147DSNK, indicative of both long-range hydrophilic softening and short-range expansion, including the hydrophilic insertion 144D. The strongly antibody producing epitopes for California 2009 [6] were all at HA1 hydropathic maxima (38–73), (318–332) or minima (158–182). Thus the hydroprofile shown here is more informative than the Euclidean structural illustration shown as an inset to Figure 2 of [6].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4309245&req=5

fig10: North Carolina response to swine flu vaccination program, which began in 2007. The small response in 2008 is greatly enhanced by 2009, after which changes were minimal. The key mutations from 2008 (ACD45795) to 2009 (ADM21399) often involve not individual sites but short strings, for instance, TATY13-16ATAN, LLISKE86-91SLSTAS, and TVT144-147DSNK, indicative of both long-range hydrophilic softening and short-range expansion, including the hydrophilic insertion 144D. The strongly antibody producing epitopes for California 2009 [6] were all at HA1 hydropathic maxima (38–73), (318–332) or minima (158–182). Thus the hydroprofile shown here is more informative than the Euclidean structural illustration shown as an inset to Figure 2 of [6].
Mentions: The large value of W, as well as the dominance of overall interactions with sialic acid on the length scale W ~ 111, explains why the details of glycosylation interactions on the length scale of glycosylation spacing (three times smaller) are important only for large-scale strain differences. A survey of 50 immunodominant epitopes (typically 15 aa long) spanning HA Calif 04/2009 revealed a distinct subset that had nearly equal autoantibody interactions almost twice as strong as the remaining epitopes [12]. There are four epitopes in this remarkable subset. As expected, all of these four occurred among the 34 epitopes in the head region below 350. The single criterion that these four (about 10% of all head epitopes studied) satisfied is that they are all either in hydrophobic or hydrophilic extrema (see also Figure 10). The likelihood of such a subset occurring accidentally is <10−7. Note that the strong interactions were equally strong for all four cases. This is what one expects, as the two kinds of extrema are weighted equally in calculating the variance, which does not depend on the sign of the deviation from average. However, the equal weighting is surprising in Euclidean terms, as the hydrophobic/hydrophilic epitopes are on the inside/outside of the globular cluster, and inside/outside are not obviously equivalent. Finally, one of the sites identified as significant by glycan microarray analysis [10] is 190, which is seen in the chain hydroprofiles (Figure 3) as one of several hydrophilic extrema.

Bottom Line: Here we show that, while HA evolution is much more complex than NA evolution, it still shows abrupt punctuation changes linked to punctuation changes of NA.HA exhibits proteinquakes, which resemble earthquakes and are related to hydropathic shifting of sialic acid binding regions.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, Rutgers University, Piscataway, NJ 08854, USA.

ABSTRACT
Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Here we show that, while HA evolution is much more complex than NA evolution, it still shows abrupt punctuation changes linked to punctuation changes of NA. 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.

Show MeSH
Related in: MedlinePlus