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Purpose <p>Tau<sup>306-311</sup>, also known as Ac-PHF6 (CH<sub>3</sub>CO-VQIVYK-NH<sub>2</sub>), is a short peptide that forms a viscous solution in water but causes instant gelation of PBS and cell culture media. Ac-PHF6 analogs wherein tyrosine’s phenolic group is substituted with phenyl or electron-deficient aromatic rings, also form hydrogels. These data indicate that the aromatic residues in these peptides may not contribute to self-assembly through their ring electronic effects, but through their hydrophobicity. We test this hypothesis by investigating Ac-PHF6 analogs wherein Tyr is substituted with several aliphatic amino acids with different side-chain hydrophobicities, <i>viz</i>. Lys, Ala, Met, Val, and Ile. Ac-PHF6* (tau<sup>275-280</sup>: CH<sub>3</sub>CO-VQIINK-NH<sub>2</sub>), an aliphatic tau hexapeptide motif similar to Ac-PHF6, was also investigated.</p> Methods <p>The peptides were synthesized via solid-phase peptide synthesis using Fmoc chemistry. Peptide stock solutions were prepared in water and diluted in PBS. The resulting PBS hydrogels were characterized using oscillatory rheology, ThT fluorescence, CD, and IR spectroscopy, while their supramolecular architectures were examined using TEM. The cytocompatibility of the peptides was evaluated using HEK-293 cells.</p> Results <p>All peptides, except for the Y310K analog, caused instant gelation of PBS. The Y310K analog formed a gel after approximately 2 h of incubation. Additionally, the Y310K hydrogel exhibited significantly lower stiffness compared to the other hydrogels. The other peptides formed hydrogels with stiffness higher than that of Ac-PHF6 hydrogel. Except for Ac-VQIVKK-am, all peptides formed amyloid-like fibrils, as revealed by ThT fluorescence spectroscopy and congo red spectral shift assay. All peptides were found to be cytocompatible with HEK-293 cells.</p> Conclusion <p>Tyr residue is not essential for Ac-PHF6 hydrogelation. Tyrosine’s contribution to Ac-PHF6 self-assembly and hydrogelation is through its hydrophobicity rather than aromaticity.</p>

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Tyr310 is Superfluous for Ac-PHF6 Hydrogelation: Ac-PHF6* is also a Hydrogelator

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Shubhangini Singh Verma,
  • Shinjini Bhattacharya,
  • Sachin Kumar,
  • Nitin Chaudhary

摘要

Purpose

Tau306-311, also known as Ac-PHF6 (CH3CO-VQIVYK-NH2), is a short peptide that forms a viscous solution in water but causes instant gelation of PBS and cell culture media. Ac-PHF6 analogs wherein tyrosine’s phenolic group is substituted with phenyl or electron-deficient aromatic rings, also form hydrogels. These data indicate that the aromatic residues in these peptides may not contribute to self-assembly through their ring electronic effects, but through their hydrophobicity. We test this hypothesis by investigating Ac-PHF6 analogs wherein Tyr is substituted with several aliphatic amino acids with different side-chain hydrophobicities, viz. Lys, Ala, Met, Val, and Ile. Ac-PHF6* (tau275-280: CH3CO-VQIINK-NH2), an aliphatic tau hexapeptide motif similar to Ac-PHF6, was also investigated.

Methods

The peptides were synthesized via solid-phase peptide synthesis using Fmoc chemistry. Peptide stock solutions were prepared in water and diluted in PBS. The resulting PBS hydrogels were characterized using oscillatory rheology, ThT fluorescence, CD, and IR spectroscopy, while their supramolecular architectures were examined using TEM. The cytocompatibility of the peptides was evaluated using HEK-293 cells.

Results

All peptides, except for the Y310K analog, caused instant gelation of PBS. The Y310K analog formed a gel after approximately 2 h of incubation. Additionally, the Y310K hydrogel exhibited significantly lower stiffness compared to the other hydrogels. The other peptides formed hydrogels with stiffness higher than that of Ac-PHF6 hydrogel. Except for Ac-VQIVKK-am, all peptides formed amyloid-like fibrils, as revealed by ThT fluorescence spectroscopy and congo red spectral shift assay. All peptides were found to be cytocompatible with HEK-293 cells.

Conclusion

Tyr residue is not essential for Ac-PHF6 hydrogelation. Tyrosine’s contribution to Ac-PHF6 self-assembly and hydrogelation is through its hydrophobicity rather than aromaticity.