Self-Assembly of Lipopeptides Containing Short Peptide Fragments Derived from the Gastrointestinal Hormone PYY(3–36): From Micelles to Amyloid Fibrils

[Image: see text] We investigate the impact of lipidation on the self-assembly of two peptide fragments from the gastrointestinal peptide hormone PYY(3–36). The lipopeptides C(16)IKPEAP and C(16)IKPEAPGE contain the first 6 and 8 amino acid residues, respectively, from the PYY(3–36) peptide sequence, with a palmitoyl C(16) tail attached at the N-terminus. These lipopeptides form spherical micelles in aqueous solution, above a critical micelle concentration (cmc), which is pH-dependent. Modeling of small-angle X-ray scattering data along with molecular dynamics simulations shows the formation of micelles with a hydrophobic interior and a well-hydrated exterior. The lipopeptides have a disordered conformation over the pH and temperature ranges studied. The cmc is found to be independent of temperature, pointing to athermal micellization. In contrast to the presence of hydrated micelles in solution, β-sheet amyloid fibrils form in dried samples. Thus, the nanostructure of lipidated PYY(3–36) fragment peptides can be tuned by control of pH or concentration, for future applications.