Substitution of tyrosine with electron-deficient aromatic amino acids improves Ac-PHF6 self-assembly and hydrogelation.

The hexapeptide PHF6 (VQIVYK), an amyloidogenic peptide stretch from human tau, self-assembles parallel in-register β-sheet formation, wherein Tyr residues are involved in aromatic stacking interactions. Ac-PHF6 (CHCO-VQIVYK-NH) forms a viscous solution in water but causes instant gelation of PBS and cell culture media. Aromatic substitutions have been reported in the literature to modulate the self-assembly of peptides. In this study, we perturbed the electronic properties of the sole aromatic residue in Ac-PHF6 and studied hydrogelation. The Tyr residue was substituted with Phe, and the phenyl moiety was then substituted with various electron-withdrawing groups at the position. All peptides caused PBS gelation with comparable rheological properties. The structures underlying the hydrogels were β-sheet fibrils. The electron-deficient aromatic moieties improved self-assembly and hydrogelation. Ac-PHF6 and no other aromatic analog except the one having -(trifluoromethyl)phenylalanine caused the gelation of deionized water. Water gelation caused by the -(trifluoromethyl)phenylalanine-containing analog is likely hydrophobicity-driven.