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Membrane structure of the human immunodeficiency virus gp41 fusion domain by molecular dynamics simulation
Shantaram Kamath1, Tuck C Wong
1Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA.
Abstract:
The structures of the 16-residue fusion domain (or fusion peptide, FP) of the human immunodeficiency virus gp41 fusion protein, two of its mutants, and a shortened peptide (5-16) were studied by molecular dynamics simulation in an explicit palmitoyloleoylphosphoethanolamine bilayer. The simulations showed that the active wild-type FP inserts into the bilayer approximately 44 degrees +/- 6 degrees with respect to the bilayer normal, whereas the inactive V2E and L9R mutants and the inactive 5 to 16 fragment lie on the bilayer surface. This is the first demonstration by explicit molecular dynamics of the oblique insertion of the fusion domain into lipid bilayers, and provides correlation between the mode of insertion and the fusogenic activity of these peptides. The membrane structure of the wild-type FP is remarkably similar to that of the influenza HA(2) FP as determined by nuclear magnetic resonance and electron spin resistance power saturation. The secondary structures of the wild-type FP and the two inactive mutants are quite similar, indicating that the secondary structure of this fusion domain plays little or no role in affecting the fusogenic activity of the fusion peptide. The insertion of the wild-type FP increases the thickness of the interfacial area of the bilayer by disrupting the hydrocarbon chains and extending the interfacial area toward the head group region, an effect that was not observed in the inactive FPs.
Insights
The human immunodeficiency virus gp41 fusion peptide (FP) inserts obliquely into lipid bilayers, a mode crucial for its fusogenic activity. Inactive mutants and fragments remain on the bilayer surface, highlighting insertion angle
Area of Science:
- Structural biology
- Biophysics
- Molecular dynamics simulations
Background:
- The gp41 fusion protein of human immunodeficiency virus mediates viral entry by fusing the viral and host cell membranes.
- Understanding the mechanism of fusion peptide (FP) insertion into lipid bilayers is critical for developing antiviral strategies.
Purpose of the Study:
- To investigate the structural basis of fusion peptide insertion into lipid bilayers.
- To correlate the mode of insertion with the fusogenic activity of the wild-type and mutant fusion peptides.
Main Methods:
- Molecular dynamics simulations of a 16-residue fusion peptide (FP) and its mutants in an explicit palmitoyloleoylphosphoethanolamine bilayer.
- Analysis of peptide insertion angles, secondary structures, and effects on bilayer interfacial properties.
Main Results:
- Active wild-type FP inserts obliquely (44° ± 6°) into the bilayer, while inactive mutants (V2E, L9R) and a shortened fragment (5-16) remain surface-bound.
- This study provides the first explicit molecular dynamics demonstration of oblique fusion domain insertion and its correlation with fusogenic activity.
- Wild-type FP insertion disrupts hydrocarbon chains, increasing interfacial thickness, an effect absent in inactive peptides.
- Secondary structures of wild-type and inactive FPs are similar, suggesting secondary structure is not the primary determinant of fusogenic activity.
Conclusions:
- Oblique insertion into lipid bilayers is a key mechanism for the fusogenic activity of the HIV gp41 fusion peptide.
- The mode of insertion, rather than secondary structure, dictates the fusogenic potential of the fusion peptide.
- These findings offer insights into viral fusion mechanisms and potential targets for antiviral drug development.