Membrane-Mimetic Micelles Drive Structural Switching in Uperin 3.5.

Uperin 3.5, an antimicrobial and amyloidogenic peptide from frog skin secretions, may represent an important evolutionary link between host-defense peptides and functional amyloids. Its ability to switch between α-helical and β-sheet conformations in membrane-associated environments makes it a compelling model for understanding how amyloidogenic sequences can acquire physiological antimicrobial roles. Microsecond-scale molecular dynamics simulations were utilized to investigate the adsorption, conformational transitions, and self-assembly behavior of Uperin 3.5 near zwitterionic DPC (dodecylphosphocholine) micelles, which mimic eukaryotic membrane environments. The DPC micelle surface promoted rapid peptide adsorption and α-helix formation, with the helical content reaching ∼40% over the simulation trajectory. Upon saturation of the micelle surface with 6-7 helical peptides, further peptide influx led to β-sheet accumulation through self-assembly at the peptide-micelle interface. This underscores the importance of the peptide-to-surfactant ratio in determining peptide aggregation behavior. The simulations also revealed a mechanism by which Uperin 3.5 peptides adopt an antiparallel cross-α, fibril-like structure near membranes with antiparallel β-sheet dimers serving as intermediate species for further helix formation. Compared with anionic interfaces, peptides near zwitterionic DPC micelles preferentially remained at the surface, offering insights into mechanisms that may mitigate cell cytotoxicity.