Chengdu Institute of Organic Chemistry , Chinese Academy of Sciences , Chengdu 610041 , China.
University of Chinese Academy of Sciences , Beijing 100049 , China.
J Am Chem Soc. 2019 Sep 11;141(36):14239-14248. doi: 10.1021/jacs.9b06094. Epub 2019 Aug 26.
Multilevel protein structures typically involve polypeptides of sufficient lengths. Here we report the folding and assembly of seven short tetrapeptides sharing the same types of α-, β-, and aromatic γ-amino acid residues. These are two sets of hybrid peptides, with three members in one set and four in the other, having complementary hydrogen-bonding sequences that were hypothesized to pair into linear H-bonded duplexes. However, instead of undergoing the anticipated pairing, the initially examined three oligomers, and or , differing only in their central αβ hybrid dipeptide sequence, do not associate with each other and exhibit distinctly different folding behavior. Experiments based on NMR and mass spectrometry, along with computational studies and systematic inference, reveal that oligomer folds into an expanded β-turn containing an unusual hybrid α/β-amino acid sequence composed of glycine and β-alanine, two α- and β-amino acid residues that are conformationally most flexible, and peptides and adopt a noncanonical, extended helical conformation and dimerize into double helices undergoing rapid conformational exchange or helix inversion. The different central dipeptide sequences, αβ vs βα, result in drastically different intramolecular H-bonding patterns that are responsible for the observed folding behavior of and . The revealed turn and double helix have few natural or synthetic counterparts, and provide novel and unique folding prototypes based on which chiral α- and β-amino acids are incorporated. The resultant derivatives , , , and follow the same folding and assembling behavior and demonstrate the generality of this system with the formation of expanded β-turns and double helices with enhanced folding stabilities, hampered helix inversion, as well as defined and dominant helical sense. This work has demonstrated the unique capability of synthetic foldamers in generating structures with fascinating folding and assembling behavior. The revealed systems offer ample opportunity for further structural optimization and applications.
多层次蛋白质结构通常涉及足够长度的多肽。在这里，我们报告了七个共享相同类型的α-、β-和芳香族γ-氨基酸残基的短四肽的折叠和组装。这些是两套混合肽，一套有三个成员，另一套有四个成员，具有互补的氢键序列，这些序列被假设为配对成线性氢键双链。然而，与预期的配对相反，最初检查的三个低聚物、或、仅在其中心αβ混合二肽序列上有所不同，它们彼此不相关，表现出明显不同的折叠行为。基于 NMR 和质谱实验、计算研究和系统推断的实验表明，低聚物折叠成含有不寻常的混合α/β-氨基酸序列的扩展β-转角，该序列由甘氨酸和β-丙氨酸组成，这两种α-和β-氨基酸残基在构象上最灵活，肽和采用非典型的扩展螺旋构象，并二聚形成经历快速构象交换或螺旋反转的双链螺旋。不同的中心二肽序列，αβ与 βα，导致截然不同的分子内氢键模式，这是导致和折叠行为的原因。所揭示的转折和双链很少有天然或合成的对应物，并且提供了新颖独特的折叠原型，基于这些原型可以掺入手性α-和β-氨基酸。所得衍生物、、、和遵循相同的折叠和组装行为，证明了该系统的通用性，形成扩展的β-转角和双链螺旋，具有增强的折叠稳定性、阻碍螺旋反转以及定义和主导的螺旋方向。这项工作展示了合成折叠物在产生具有迷人折叠和组装行为的结构方面的独特能力。所揭示的系统为进一步的结构优化和应用提供了充足的机会。
