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 peptide self-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)(2) peptide 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.

Self-assembly of amphiphilic peptides: Effects of the single-chain-to-gemini structural transition and the side chain groups

“…The CAC decrease with increasing molecular hydrophobicity is the same as in the case of traditional surfactants [38]. This trend is easily understood to know that hydrophobic interaction is an important force in driving the peptide self-assembly, and increase in molecular hydrophobicity would enhance hydrophobic interaction and thus to promote molecular aggregation at lower concentrations [39]. Such a trend could also be rationalized with modified packing parameter equation as presented in our previous work [18].…”

Controlling network topology and mechanical properties of co‐assembling peptide hydrogels

“…[24][25][26][27][28][29] In the former molecule, the di-glycine spacer was included to promote flexibility between the two octapeptides, and the order of amino acids was specifically designed to include a charge repulsion around the central glycine units to minimize any intra-molecular folding of the extended peptide chain (Figure 1), thus enhancing the ability of FEKII18 to co-assemble into two different fibers of FEKII. Prior to any doping experiments, the characteristic self-assembling behavior of the pure FEKII18 peptide was explored and compared to our previous work on the single FEKII peptide.…”

Rational design of fiber forming supramolecular structures

“…Notably, the Nilsson group has utilized p-p and hydrophobic sidechain interactions to demonstrate the formation of selfassembled materials inspired by amyloid materials. [89][90][91] To set the stage for his future work, Nilsson demonstrated that aromatic residues and p-p stacking interactions were not strictly necessary for amyloid formation with the amphipathic sequence (FKFE) 2 . 89,91 Instead, residues with sufficient hydrophobicity or b-sheet propensity could drive amyloid fibril formation.…”

“…[89][90][91] To set the stage for his future work, Nilsson demonstrated that aromatic residues and p-p stacking interactions were not strictly necessary for amyloid formation with the amphipathic sequence (FKFE) 2 . 89,91 Instead, residues with sufficient hydrophobicity or b-sheet propensity could drive amyloid fibril formation. When non-aromatic, highly hydrophobic cyclohexylalanine was substituted for phenylalanine residues, self-assembly still occurred and even exhibited enhanced hydrogelation properties.…”