Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Am Chem Soc. 2010 Oct 6;132(39):13879-85. doi: 10.1021/ja1062532.
Helices are the most extensively studied secondary structures formed by β-peptide foldamers. Among the five known β-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of α-peptide helices (α-helix and 3(10)-helix). The β-peptide 12-helix is defined by i, i+3 C═O···H-N backbone hydrogen bonds and promoted by β-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate β-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical β-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical β-peptides, all containing residues that bear side chains. Four of the crystallized β-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a β(3)-hPhe residue. These five β-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of β-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C═O···H-N hydrogen-bonded helices formed by other peptide backbones generated from α- and/or β-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a β(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of β-amino acids.
螺旋是β-肽折叠体形成的研究最多的二级结构。在已知的五种β-肽螺旋中，12-螺旋特别有趣，因为其内部氢键取向和宏观偶极子类似于α-肽螺旋（α-螺旋和 3(10)-螺旋）。β-肽 12-螺旋由 i, i+3 C═O···H-N 主链氢键定义，并由具有五元环约束的β-残基促进。12-螺旋支架已被用于生成具有特定生物学功能的β-肽，对于这些肽，各种侧链必须沿主链正确放置，并且在折叠时在空间中正确排列。以前仅报道了两种 12-螺旋β-肽的晶体结构，都是反式-2-氨基环戊烷羧酸（ACPC）的同聚物。在这里，我们报告了另外五个 12-螺旋β-肽的晶体结构，所有这些结构都包含带有侧链的残基。结晶的四个β-肽都包含反式-4,4-二甲基-2-氨基环戊烷羧酸（dm-ACPC）残基，而第五个则包含β(3)-hPhe 残基。这五个β-肽在固态下都采用完全折叠的 12-螺旋构象。新的晶体结构以及以前的报告数据允许对 12-螺旋构象进行详细表征；推导了β-残基的平均主链扭转角和螺旋参数。发现这些结构参数与由α-和/或β-氨基酸生成的其他肽骨架形成的 i, i+3 C═O···H-N 氢键合螺旋的参数相似。dm-ACPC 和 ACPC 的构象行为的相似性与以前基于 NMR 的结论一致，即 4,4-二取代的 ACPC 衍生物与 12-螺旋折叠相容。此外，我们的数据显示了β(3)-残基如何适应 12-螺旋，从而增强了对这一灵活的β-氨基酸类别的多样化构象行为的理解。
