Environmental control of antimicrobial-to-amyloid switching in amphipathic peptides.

Abstract

Antimicrobial peptides capable of functional amyloid formation exhibit pronounced environmental sensitivity, yet the physicochemical principles governing their structural switching remain poorly understood. The antimicrobial peptide-to-amyloid transition of Uperin 3.5, a conformationally plastic amphibian antimicrobial peptide, was investigated using an integrated approach combining all-atom molecular dynamics simulations with circular dichroism and thioflavin T fluorescence measurements. The effects of surfactant charge, assembly state, peptide stoichiometry, and ionic strength on peptide structural switching were systematically examined. The results revealed a mechanistic competition between peptide-surfactant stabilisation and cooperative peptide self-assembly that governed the conformational fate of the system. Under conditions of high surfactant availability, including micellar environments above the critical micelle concentration (CMC), peptides preferentially adopted α-helical amphipathic conformations associated with antimicrobial function. Helix stabilisation followed a clear charge-dependent hierarchy, with anionic SDS producing the strongest effect, followed by zwitterionic DPC, while cationic CTAB failed to induce substantial structural remodelling. In contrast, below-CMC conditions promoted cooperative aggregation through surfactant-mediated peptide assembly. Under these conditions, dispersed SDS monomers acted as dynamic co-assembly scaffolds that locally concentrated peptides, partially screened electrostatic repulsion, and nucleated N-terminal β-sheet interactions. Ionic screening further accelerated this process, producing structurally heterogeneous α/β aggregates. Together, these findings establish peptide stoichiometry and surfactant assembly dynamics as key regulators of environment-responsive structural switching in amphipathic peptides. More broadly, this work provides a mechanistic framework linking amphiphile availability, electrostatic screening, and cooperative self-assembly to functional amyloidogenesis in membrane-active peptides.

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