Cooperative Intramolecular Hydrogen Bonding Strongly Enforces cis-Peptoid Folding

Sequence-defined peptoids, or N-substituted
glycines,
are an attractive class of bioispired polymer due to their biostability
and efficient synthesis. However, the de novo design of folded peptoids with precise three-dimensional structures
has been hindered by limited means to deterministically control backbone
conformation. Peptoid folds are generally destabilized by the cis/trans backbone-amide isomerization,
and few side-chains are capable of enforcing a specific amide conformation.
Here, we show that a novel class of cationic alkyl ammonium ethyl
side-chains demonstrates significant enforcement of the cis-amide backbone (Kcis/trans up to 70) using an unexpected ensemble of weak
intramolecular CH–O and/or NH–O hydrogen bonds between
the side-chain and the backbone carbonyl moieties. These interactions
are evidenced by X-ray crystallography, variable-temperature NMR spectroscopy,
and DFT calculations. Moreover, these side-chains are inexpensive,
structurally diverse, hydrophilic, and can be integrated into
longer peptoid sequences via solid-phase synthesis. Notably, we extended
these concepts to synthesize a water-soluble peptoid 10-mer that adopts
one predominant fold in solution, as determined by multidimensional
NMR spectroscopy. This decamer, to the best of our knowledge, is the
longest linear peptoid sequence atomically characterized to retain
a well-folded structure. These findings fill a critical gap in peptoid
folding and should propel the development of peptoid applications
in a broad range of contexts, from pharmaceutical to material sciences.

序列定义的肽片段，或称N-取代甘氨酸，是一类极具吸引力的生物启发型聚合物，因其生物稳定性和高效的合成特性而备受青睐。然而，精确三维结构折叠的肽片段的原生设计受到了控制骨架构象的有限手段的阻碍。肽片段的折叠通常因顺反骨架酰胺异构化而变得不稳定，且很少有侧链能够强制特定的酰胺构象。在本研究中，我们发现一类新型阳离子烷基铵乙基侧链通过侧链与骨架羰基部分之间意外形成的弱分子内CH-O和/或NH-O氢键群，显著地强制了顺式酰胺骨架（Kcis/trans高达70）。这些相互作用通过X射线晶体学、变温核磁共振波谱和DFT计算得到了证实。此外，这些侧链价格低廉、结构多样、亲水性强，可以通过固相合成集成到更长的肽片段序列中。值得注意的是，我们扩展了这些概念，合成了可溶于水的10-肽片段，该片段在溶液中采用了一种主要的折叠形式，这是通过多维核磁共振波谱确定的。据我们所知，这种十肽是迄今为止原子级表征的、能够保持良好折叠结构的线性肽片段序列中最长的。这些发现填补了肽片段折叠领域的关键空白，并应推动肽片段在从药物学到材料科学等广泛领域的应用发展。