The effect of increasing hydrophobicity on the self-assembly of amphipathic β-sheet peptides

Abstract

Peptide self-assembly processes are central to the etiology of amyloid diseases. Much effort has been devoted to characterizing amyloid structure and the mechanisms of peptideself-assembly leading to amyloid. It has been proposed that aromatic side-chain interactions play a central role in early self-assembly recognition events, but this contention remains somewhat controversial. Recent studies have indicated that in some amyloid peptides, aromatic residues can be exchanged for other hydrophobic residues and these nonaromatic variant peptides still retain competency to form amyloid, although with attenuated kinetics. In an effort to understand the relative contributions of aromatic versus generic hydrophobic interactions, studies to quantify the self-assembly properties of amyloid peptides as a function of increasing hydrophobicity and altered aromatic character have been undertaken. In the present study, the amphipathic (FKFE)₂peptide has been chosen as a model system. The aromatic phenylalanine residues have been globally replaced with nonaromatic natural residues with lower hydrophobicity (alanine, valine, and leucine) and a nonnatural residue with greater hydrophobicity (cyclohexylalanine). The self-assembly properties of these peptides have been characterized by secondary structure analysis and microscopic analysis of the resulting aggregate structures. These studies confirm that aromatic interactions are not strictly required for amyloid formation and that the nonaromatic, but highly hydrophobic, cyclohexylalanine appears to have unique self-assembly characteristics and enhanced hydrogelation properties. The aromatic phenylalanine-containing peptide displays intriguing solvent- and concentration-dependent polymorphism, suggesting that aromatic interactions, while not essential for self-assembly, may give rise to unique structural features.