Krieger Viktoria, Ciglia Emanuele, Thoma Roland, Vasylyeva Vera, Frieg Benedikt, de Sousa Amadeu Nader, Kurz Thomas, Janiak Christoph, Gohlke Holger, Hansen Finn K
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.
Institute of Inorganic and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.
Chemistry. 2017 Mar 13;23(15):3699-3707. doi: 10.1002/chem.201605100. Epub 2017 Feb 13.
α-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis/trans-amide bond conformers, which contribute to the high flexibility of α-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Herein, we have performed the first thorough analysis of the folding propensities of α-aminoxy peptoids (or N-substituted 2-aminoxyacetic acid oligomers). To this end, the amide bond geometry and the conformational properties of a series of model α-aminoxy peptoids were investigated by using 1D and 2D NMR experiments, X-ray crystallography, natural bond orbital (NBO) analysis, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix. Given their ease of synthesis and conformational properties, α-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity.
α-类肽，即N-取代甘氨酸低聚物，是一类重要的具有蛋白水解稳定性的拟肽折叠体。然而，顺式/反式酰胺键构象异构体的存在导致α-类肽具有高度灵活性，这被认为是一个主要缺点。因此，一种能更好地控制酰胺键几何结构的修饰类肽主链可能有助于克服这一限制。在此，我们首次对α-氨氧基类肽（或N-取代2-氨氧基乙酸低聚物）的折叠倾向进行了全面分析。为此，通过一维和二维核磁共振实验、X射线晶体学、自然键轨道（NBO）分析、圆二色（CD）光谱以及分子动力学（MD）模拟，研究了一系列模型α-氨氧基类肽的酰胺键几何结构和构象性质，结果表明即使在没有顺式导向侧链的情况下，它们也对顺式酰胺键有独特的偏好。基于分子动力学模拟的构象分析表明，α-氨氧基类肽可以采用螺旋构象，这种构象能够模拟典型α-螺旋中肽侧链的空间排列。鉴于其易于合成的特点和构象性质，α-氨氧基类肽代表了类肽家族的一个新成员，它能够控制酰胺异构现象，同时保持侧链多样性的潜力。
