Crystallographic Characterization of Helical Secondary Structures in α/β-Peptides with 1:1 Residue Alternation

Oligomers that contain both α- and β-amino acid residues in a 1:1 alternating pattern have recently been shown by several groups to adopt helical secondary structures in solution. The β-residue substitution pattern has a profound effect on the type of helix formed and the stability of the helical conformation. On the basis of two-dimensional NMR data, we have previously proposed that β-residues with a five-membered ring constraint promote two different types of α/β-peptide helix. The “11-helix” contains i,i+3 CO···H−N hydrogen bonds between backbone amide groups; these hydrogen bonds occur in 11-atom rings. The α/β-peptide “14/15-helix” contains i,i+4 CO···H−N hydrogen bonds, which occur in alternating 14- and 15-atom rings. Here we provide crystallographic data for 14 α/β-peptides that form the 11-helix and/or the 14/15-helix. These results were obtained for a series of oligomers containing β-residues derived from (S,S)-trans-2-aminocyclopentanecarboxylic acid (ACPC) and α-residues derived from α-aminoisobutyric acid (Aib) or l-alanine (Ala). The crystallized α/β-peptides range in length from 4 to 10 residues. Nine of the α/β-peptides display the 11-helix in the solid state, three display the 14/15-helix, and two display conformations that contain both i,i+3 and i,i+4 CO···H−N hydrogen bonds, but not bifurcated hydrogen bonds. Only 3 of the 14 crystal structures presented here have been previously described. These results suggest that longer α/β-peptides prefer the 14/15-helix over the 11-helix, a conclusion that is consistent with previously reported NMR data obtained in solution.

近期已有多个研究团队证实，以1:1交替模式同时包含α-氨基酸残基（α-amino acid residues）与β-氨基酸残基（β-amino acid residues）的寡聚物（oligomers）可在溶液中形成螺旋二级结构（helical secondary structures）。β残基的取代模式对所形成螺旋的类型及螺旋构象的稳定性具有显著影响。基于二维核磁共振（two-dimensional NMR）数据，我们此前曾提出：带有五元环约束的β残基可诱导两种不同类型的α/β-肽螺旋。“11螺旋”的主链酰胺基团之间存在i,i+3型C=O···H−N氢键，该氢键由11原子环构成；而α/β-肽“14/15螺旋”则包含i,i+4型C=O···H−N氢键，该氢键交替出现在14原子环与15原子环中。本文提供了14种可形成11螺旋和/或14/15螺旋的α/β-肽的晶体学数据（crystallographic data）。这些结果来自一系列寡聚物，其β残基衍生自(S,S)-反式-2-氨基环戊烷羧酸（ACPC），α残基则衍生自α-氨基异丁酸（Aib）或L-丙氨酸（Ala）。所结晶的α/β-肽长度介于4至10个残基之间。其中9种α/β-肽在固态下呈现11螺旋构象，3种呈现14/15螺旋构象，另有2种的构象同时包含i,i+3与i,i+4型C=O···H−N氢键，但不存在分叉氢键（bifurcated hydrogen bonds）。本文所呈现的14个晶体结构中，仅有3个曾在以往研究中被报道。上述结果表明，较长的α/β-肽更倾向于形成14/15螺旋而非11螺旋，这一结论与此前溶液中二维核磁共振研究所得结果一致。