Expanding the amyloid landscape: structural plasticity of antimicrobial peptides

Amyloids, once viewed solely as pathological aggregates, are now recognized as dynamic assemblies that underpin a broad range of biological functions. Using a computational platform integrated with biophysical, functional, and cryo-EM analyses, we expand the amyloid landscape by identifying fifteen new fibril-forming antimicrobial and virulent natural peptides that exhibit exceptional structural plasticity. These peptides switch between α-helical and β-sheet architectures in response to environmental cues, with biological activity correlating strongly with α-helicity. High-resolution cryo-EM structures of the amphibian antimicrobial peptides aurein 1.2 and brevinin-1OKc reveal multiple cross-β polymorphs stabilized by kinked β-sheets, aromatic anchors, and complex steric-zipper interfaces, including a distinctive six-pointed, radially symmetric, snowflake-like architecture. Together, these findings demonstrate that sequence-encoded aggregation dynamics regulate biological activity, linking structural polymorphism, environmental responsiveness, and function across the amyloid continuum. This work establishes a molecular framework for reversible and environmentally responsive functional amyloids, offering new principles for understanding adaptive host–pathogen interactions and for the rational design of biofunctional peptide materials.