Sequence-specific conformational dynamics of model transmembrane domains determines their membrane fusogenic function

Area of Science:

• Biochemistry
• Structural Biology
• Membrane Biophysics

Background:

• Transmembrane domains of fusion proteins are critical for function.
• These domains often contain helix-destabilizing residues like isoleucine (Ile) and valine (Val).
• A correlation exists between fusogenicity and helix stability.

Purpose of the Study:

• To systematically investigate the relationship between membrane fusogenicity and helix stability.
• To probe the conformational dynamics of model peptides using amide deuterium/hydrogen exchange.
• To map functionally relevant subdomains within the hydrophobic core of fusion peptides.

Main Methods:

• Design and synthesis of LV peptides with varying ratios of Leu and Val residues.
• Monitoring amide deuterium/hydrogen exchange kinetics to assess peptide conformational dynamics.
• Analysis of novel peptide variants with concentrated Val residues at peripheral or central domains.

Main Results:

• Fusogenicity of LV peptides increases with higher content of helix-destabilizing residues.
• Amide deuterium exchange kinetics correlate with helix destabilization and fusogenicity.
• Peptides with faster deuterium exchange rates in specific subpopulations exhibit enhanced fusogenicity.
• Dynamic domains near helix termini are more critical for fusogenicity than central domains.

Conclusions:

• Helix destabilization and specific conformational dynamics are key to membrane fusion.
• The positioning of helix-destabilizing residues, particularly at termini, significantly impacts fusogenicity.
• Cooperation between dynamic terminal and central domains is essential for maximal fusogenicity.