Membrane-Mimetic Micelles Drive Structural Switching in Uperin 3.5

Area of Science:

• Biochemistry
• Biophysics
• Molecular Biology

Background:

• Uperin 3.5, a peptide from frog skin, exhibits both antimicrobial and amyloidogenic properties.
• Its conformational flexibility between alpha-helical and beta-sheet structures is key to its physiological roles.
• Understanding this peptide is crucial for exploring the link between host-defense peptides and functional amyloids.

Purpose of the Study:

• To investigate the adsorption, conformational changes, and self-assembly of Uperin 3.5 near membrane-mimicking environments.
• To elucidate the mechanism of Uperin 3.5's structural transitions and aggregation near zwitterionic interfaces.
• To compare its behavior at zwitterionic versus anionic interfaces for insights into cytotoxicity.

Main Methods:

• Microsecond-scale molecular dynamics simulations.
• Utilized dodecylphosphocholine (DPC) micelles to mimic eukaryotic membrane environments.
• Analyzed peptide adsorption, conformational transitions (alpha-helix to beta-sheet), and self-assembly at the peptide-micelle interface.

Main Results:

• DPC micelle surface facilitated rapid Uperin 3.5 adsorption and alpha-helix formation (approx. 40% helical content).
• At higher peptide concentrations (6-7 peptides/micelle), beta-sheet accumulation occurred via self-assembly.
• A cross-alpha, fibril-like structure with antiparallel beta-sheet dimers as intermediates was observed.
• Peptides remained surface-associated at zwitterionic DPC micelles, unlike behavior at anionic interfaces.

Conclusions:

• The peptide-to-surfactant ratio significantly influences Uperin 3.5 aggregation.
• Uperin 3.5 adopts specific structures near membranes, potentially mitigating cytotoxicity.
• This study provides a molecular-level understanding of how antimicrobial peptides transition into functional amyloids.