Short peptides composed of naturally occurring amino acids are usually unstructured in aqueous media. The installation of covalent constraints within their side chains or backbones, resulting in the formation of macrocyclic peptides, is an appealing approach to stabilize them in defined secondary structures. Therefore, with the objective to stabilize α-turn conformation, we designed, synthesized and characterized constrained 13-membered macrocyclic peptides. Their design was inspired by previous work using the replacement of a hydrogen bond by a covalent bond, for the stabilization of α-helical secondary structures. Their synthesis employed our recently published solid-phase method based on Fukuyama–Mitsunobu alkylation reactions. We report herein an optimized synthesis leading to three water-soluble 13-membered macrocyclic peptides 10a–c, including respectively two, one and zero glycine residues. They were characterized by CD and NMR, which indicated the presence of equilibrating conformers. The detailed conformational analysis was based on extensive NMR and molecular dynamics studies. We found that the peptide without glycine residues 10c was mostly present as slowly interconverting conformers whereas the peptide with two glycine residues 10a was mostly present as rapidly interconverting conformers. We did not find a good match between the conformers of 10a and α-turns occurring in proteins, due to the high flexibility of the glycine backbone. Interestingly, we found that the major conformer of 10c accurately matched the “non-classical” or “tight” α-turn of type II-α_LS, with a RMSD value of 0.42 Å for heavy atoms constituting the macrocycle. This is, to the best of our knowledge, the first molecule reported to mimic this type of α-turn found in proteins.

中文翻译：

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合成和水溶性大环肽稳定蛋白α形转弯的表征†

由天然氨基酸组成的短肽通常在水性介质中是非结构化的。共价约束在其侧链或主链中的安装，导致大环肽的形成，是一种使它们稳定在确定的二级结构中的吸引人的方法。因此，以稳定α-转角构象为目标，我们设计，合成和表征了受约束的13元大环肽。他们的设计受到以前工作的启发，该工作使用氢价键替换为共价键来稳定α-螺旋二级结构。他们的合成采用了我们最近发表的基于福山-Mitsunobu烷基化反应的固相方法。我们在此报告了导致三种水溶性13元大环肽的优化合成10a–c，分别包括两个，一个和零个甘氨酸残基。它们通过CD和NMR表征，表明存在平衡构象异构体。详细的构象分析基于广泛的NMR和分子动力学研究。我们发现没有甘氨酸残基10c的肽主要以缓慢互变构象体存在，而具有两个甘氨酸残基10a的肽主要以快速互构构象体存在。由于甘氨酸骨架的高度灵活性，我们没有发现蛋白质中出现的10a构象构象与α-转角之间的良好匹配。有趣的是，我们发现10c的主要构象对于构成大环的重原子，精确地匹配了II- αLS型的“非经典”或“紧”型α_弯，RMSD值为0.42。据我们所知，这是第一个报道的模仿蛋白质中这种类型的α-转角的分子。