Effects of Varied Sequence Pattern on the Self-Assembly of Amphipathic Peptides

Amphipathic peptides have an increased propensity to self-assemble into amyloid-like β-sheet fibrils when their primary sequence pattern consists of alternating hydrophobic and hydrophilic amino acids. These fibrils adopt a bilayer architecture composed of two β-sheets laminated to bury the hydrophobic side chains of the β-sheet in the bilayer interior, leaving the hydrophilic side chains exposed at the bilayer surface. In this study, the effects of altering the sequence pattern of amphipathic peptides from strictly alternating hydrophobic/hydrophilic repeats to more complex patterning of hydrophobic and hydrophilic residues on self-assembly of the resulting sequences is reported. Self-assembly of the Ac-(FKFE)₂-NH₂ peptide was compared to that of four related sequences with varied amino acid sequence patterning: Ac-(FK)₂(FE)₂-NH₂, Ac-KEFFFFKE-NH₂, Ac-(KFFE)₂-NH₂, and Ac-FFKEKEFF-NH₂. The Ac-(FKFE)₂-NH₂ and Ac-(FK)₂(FE)₂-NH₂ peptides effectively self-assembled at high (1.0 mM) and low (0.2 mM) concentrations (pH 3–4) into β-sheet nanoribbons that were 8 and 4 nm wide, respectively. The Ac-KEFFFFKE-NH₂ peptide failed to self-assemble at low concentration (pH 3–4), but self-assembled into distinct nanotapes that were ∼20 nm in width at high concentration. Ac-(KFFE)₂-NH₂ and Ac-FFKEKEFF-NH₂ failed to self-assemble into fibril/tape-like materials at either high or low concentration at pH 3–4, although Ac-FFKEKEFF-NH₂ formed micelle-like aggregates at higher concentrations. At neutral pH, similar self-assembly behavior was observed for each peptide as was observed at acidic pH. An exception was the Ac-FFKEKEFF-NH₂ peptide, which formed ∼20 nm nanotapes at neutral pH. These results indicate that amino acid sequence patterns exert a profound influence on self-assembly propensity and morphology of the resulting materials even when the overall hydrophobicity or charge of the related peptides are identical. Sequence pattern variation can thus be exploited as a variable in the creation of novel materials composed of self-assembled peptides