Amphipathic peptides with alternating polar and nonpolar amino acid sequences efficiently self-assemble into functional β-sheet fibrils as long as the nonpolar residues have sufficient hydrophobicity. For example, the Ac-(FKFE)2 -NH2 peptide rapidly self-assembles into β-sheet bilayer nanoribbons, while Ac-(AKAE)2 -NH2 fails to self-assemble under similar conditions due to the significantly reduced hydrophobicity and β-sheet propensity of Ala relative to Phe. Herein, we systematically explore the effect of substituting only two of the four Ala residues at various positions in the Ac-(AKAE)2 -NH2 peptide with amino acids of increasing hydrophobicity, β-sheet potential, and surface area (including Phe, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), cyclohexylalanine (Cha), and pentafluorophenylalanine (F5 -Phe)) on the self-assembly propensity of the resulting sequences. It was found that double Phe variants, regardless of the position of substitution, failed to self-assemble under the conditions used in this study. In contrast, all double 1-Nal and 2-Nal variants readily self-assembled, albeit at differing rates depending on the substitution patterns. To determine whether this was due to hydrophobicity or side chain surface area, we also prepared double Cha and F5 -Phe variant peptides (both side chain groups are more hydrophobic than Phe). Each of these variants also underwent effective self-assembly, with the aromatic F5 -Phe peptides doing so with greater efficiency. These findings provide insight into the role of amino acid hydrophobicity and sequence pattern on self-assembly proclivity of amphipathic peptides and on how targeted substitutions of nonpolar residues in these sequences can be exploited to tune the characteristics of the resulting self-assembled materials.

中文翻译：

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平衡疏水性和序列模式以影响两亲性肽的自组装。

只要非极性残基具有足够的疏水性，具有交替的极性和非极性氨基酸序列的两亲性肽就可以有效地自组装成功能性β-折叠原纤维。例如，Ac-（FKFE）2-NH2肽快速自组装成β-折叠双层纳米带，而Ac-（AKAE）2-NH2在相似条件下由于疏水性和β-明显降低而无法自组装。丙氨酸相对于苯丙氨酸的表层倾向。在本文中，我们系统地研究了用疏水性，β-片层电位和表面积（包括Phe，1）增加的氨基酸取代Ac-（AKAE）2-NH2肽中不同位置的四个Ala残基中的两个残基的作用。 -萘丙氨酸（1-Nal），2-萘丙氨酸（2-Nal），环己基丙氨酸（Cha），和五氟苯丙氨酸（F5-Phe））对所得序列的自组装倾向。发现在该研究中使用的条件下，无论取代位置如何，双Phe变体均无法自组装。相反，所有双1-Nal和2-Nal变体都容易自组装，尽管根据取代模式以不同的速率进行。为了确定这是由于疏水性还是侧链表面积引起的，我们还制备了双Cha和F5-Phe变体肽（两个侧链基团均比Phe更疏水）。这些变体中的每一个也都进行了有效的自组装，而芳香族的F5-Phe肽则具有更高的效率。