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Helical hairpin structure of influenza hemagglutinin fusion peptide stabilized by charge-dipole interactions between the N-terminal amino group and the second helix.

Abstract
The fusion domain of the influenza coat protein hemagglutinin HA2, bound to dodecyl phosphocholine micelles, was recently shown to adopt a structure consisting of two antiparallel α-helices, packed in an exceptionally tight hairpin configuration. Four interhelical H(α) to C═O aliphatic H-bonds were identified as factors stabilizing this fold. Here, we report evidence for an additional stabilizing force: a strong charge-dipole interaction between the N-terminal Gly(1) amino group and the dipole moment of helix 2. pH titration of the amino-terminal (15)N resonance, using a methylene-TROSY-based 3D NMR experiment, and observation of Gly(1 13)C' show a strongly elevated pK = 8.8, considerably higher than expected for an N-terminal amino group in a lipophilic environment. Chemical shifts of three C-terminal carbonyl carbons of helix 2 titrate with the protonation state of Gly(1)-N, indicative of a close proximity between the N-terminal amino group and the axis of helix 2, providing an optimal charge-dipole stabilization of the antiparallel hairpin fold. pK values of the side-chain carboxylate groups of Glu(11) and Asp(19) are higher by about 1 and 0.5 unit, respectively, than commonly seen for solvent-exposed side chains in water-soluble proteins, indicative of dielectric constants of ε = ∼30 (Glu(11)) and ∼60 (Asp(19)), placing these groups in the headgroup region of the phospholipid micelle.
AuthorsJustin L Lorieau, John M Louis, Ad Bax
JournalJournal of the American Chemical Society (J Am Chem Soc) Vol. 133 Issue 9 Pg. 2824-7 (Mar 09 2011) ISSN: 1520-5126 [Electronic] United States
PMID21319795 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Hemagglutinins, Viral
  • Peptides
Topics
  • Amino Acid Sequence
  • Hemagglutinins, Viral (chemistry)
  • Humans
  • Influenza A virus (chemistry)
  • Influenza, Human (virology)
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides (chemistry)
  • Protein Structure, Secondary

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