Abstract
The fusion peptide EBO(16) (GAAIGLAWIPYFGPAA) comprises the fusion domain of an internal sequence located in the envelope fusion glycoprotein (GP2) of the Ebola virus. This region interacts with the cellular membrane of the host and leads to membrane fusion. To gain insight into the mechanism of the peptide-membrane interaction and fusion, insertion of the peptide was modeled by experiments in which the tryptophan fluorescence and (1)H NMR were monitored in the presence of sodium dodecyl sulfate micelles or in the presence of detergent-resistant membrane fractions. In the presence of SDS micelles, EBO(16) undergoes a random coil-helix transition, showing a tendency to self-associate. The three-dimensional structure displays a 3(10)-helix in the central part of molecule, similar to the fusion peptides of many known membrane fusion proteins. Our results also reveal that EBO(16) can interact with detergent-resistant membrane fractions and strongly suggest that Trp-8 and Phe-12 are important for structure maintenance within the membrane bilayer. Replacement of tryptophan 8 with alanine (W8A) resulted in dramatic loss of helical structure, proving the importance of the aromatic ring in stabilizing the helix. Molecular dynamics studies of the interaction between the peptide and the target membrane also corroborated the crucial participation of these aromatic residues. The aromatic-aromatic interaction may provide a mechanism for the free energy coupling between random coil-helical transition and membrane anchoring. Our data shed light on the structural "domains" of fusion peptides and provide a clue for the development of a drug that might block the early steps of viral infection.
Highlights
To check for the presence of proline isomerization, the connectivities between Ile-9 and Pro-10 residues or Gly-13 and Pro-14 were available
In this work we suggest that glycines may be located on the same face before and after the reflecting the random nature and high degree of backbone helix, close to polar groups of the lipid bilayer, improving an mobility of SDS micelles binding structure (Fig. 5D)
A simulation time of 4 The peptide-membrane interaction has been extensively ns was sufficient to reveal the interaction between EBO16 and characterized for influenza virus fusion peptide, which exhibits the SDS micelle (Fig. 6A)
Summary
To check for the presence of proline isomerization, the connectivities between Ile-9 and Pro-10 residues or Gly-13 and Pro-14 were available. The backbone structures of the lowest energy conformers of EBO16 in SDS micelles at pH 7.0 are shown (Fig. 3B). The data indicate a small tional changes in the presence of liposomes prepared with tendency for the peptide to assume a helical conformation from mixed lipid composition and from DRMs (Fig. 4).
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