Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, CNRS-Université Montpellier-ENSCM, 34093, Montpellier cedex 5, France.
CRM2, UMR 7063 CNRS Université de Lorraine, Boulevard des Aiguilletes, 54506, Vandoeuvre-lès-Nancy Cedex, France.
Chemistry. 2018 Dec 12;24(70):18795-18800. doi: 10.1002/chem.201804404. Epub 2018 Nov 15.
12/10-Helices constitute suitable templates that can be used to design original structures. Nevertheless, they often suffer from a weak stability in polar solvents because they exhibit a mixed hydrogen-bond network resulting in a small macrodipole. In this work, stable and functionalizable 12/10-helices were developed by alternating a highly constrained β -trisubstituted bicyclic amino acid (S)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid ((S)-ABOC) and an acyclic substituted β-homologated proteinogenic amino acid (l-β -hAA). Based on NMR spectroscopic analysis, it was shown that such mixed β-peptides display well-defined right-handed 12/10-helices in polar, apolar, and chaotropic solvents; that are, CD OH, CDCl , and [D ]DMSO, respectively. The stability of the hydrogen bonds forming the C and C pseudocycles as well as the benefit provided by the use of the constrained bicyclic ABOC versus typical acyclic β-amino acids sequences when designing 12/10-helix were investigated using NH/ND NMR exchange experiments and DFT calculations in various solvents. These studies showed that the β -hAA/(S)-ABOC helix displayed a more stable hydrogen-bond network through specific stabilization of the C pseudocycles involving the bridgehead NH of the ABOC bicyclic scaffold.
12/10-螺旋构成了合适的模板，可以用来设计原始结构。然而，它们在极性溶剂中通常稳定性较弱，因为它们表现出混合的氢键网络，导致小的宏观偶极子。在这项工作中，通过交替使用高度约束的β-三取代双环氨基酸（S）-1-氨基双环[2.2.2]辛烷-2-羧酸（（S）-ABOC）和非环取代的β-同系化蛋白氨基酸（l-β-hAA），开发了稳定且可功能化的 12/10-螺旋。基于 NMR 光谱分析，表明这种混合β-肽在极性、非极性和离液溶剂中均显示出定义明确的右手 12/10-螺旋；即 CDOH、CDCl 和 [D ]DMSO。使用约束双环 ABOC 与典型的非环β-氨基酸序列设计 12/10-螺旋时，形成 C 和 C 伪环的氢键的稳定性以及氢键的稳定性通过 NH/ND NMR 交换实验和不同溶剂中的 DFT 计算进行了研究。这些研究表明，β-hAA/（S）-ABOC 螺旋通过涉及 ABOC 双环支架桥接 NH 的 C 伪环的特定稳定化，显示出更稳定的氢键网络。
