Verma Shubhangini Singh, Chaudhary Nitin
a, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati Guwahati 781 039 India
RSC Adv. 2025 Jun 30;15(28):22216-22227. doi: 10.1039/d5ra03251b.
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.
六肽PHF6（VQIVYK）是一种来自人tau蛋白的淀粉样生成肽段，能自组装形成平行的同向β-折叠结构，其中Tyr残基参与芳香族堆积相互作用。乙酰化的PHF6（CHCO-VQIVYK-NH）在水中形成粘性溶液，但能使PBS和细胞培养基瞬间凝胶化。文献报道芳香族取代可调节肽的自组装。在本研究中，我们改变了乙酰化PHF6中唯一芳香族残基的电子性质并研究了水凝胶化过程。将Tyr残基替换为Phe，然后在苯环上的特定位置用各种吸电子基团进行取代。所有肽都能使PBS凝胶化，且具有相似的流变学性质。水凝胶的基础结构是β-折叠原纤维。缺电子的芳香族部分改善了自组装和水凝胶化。乙酰化PHF6以及除含有-(三氟甲基)苯丙氨酸的类似物外的其他芳香族类似物均未导致去离子水凝胶化。含-(三氟甲基)苯丙氨酸的类似物引起的水凝胶化可能是由疏水性驱动的。
