Molecular Engineering of the Peptoid Nanosheet Hydrophobic Core

The relationship between the structure of sequence-defined peptoid polymers and their ability to assemble into well-defined nanostructures is important to the creation of new bioinspired platforms with sophisticated functionality. Here, the hydrophobic N-(2-phenylethyl)­glycine (Npe) monomers of the standard nanosheet-forming peptoid sequence were modified in an effort to (1) produce nanosheets from relatively short peptoids, (2) inhibit the aggregation of peptoids in bulk solution, (3) increase nanosheet stability by promoting packing interactions within the hydrophobic core, and (4) produce nanosheets with a nonaromatic hydrophobic core. Fluorescence and optical microscopy of individual nanosheets reveal that certain modifications to the hydrophobic core were well tolerated, whereas others resulted in instability or aggregation or prevented assembly. Importantly, we demonstrate that substitution at the meta and para positions of the Npe aromatic ring are well tolerated, enabling significant opportunities to tune the functional properties of peptoid nanosheets. We also found that N-aryl glycine monomers inhibit nanosheet formation, whereas branched aliphatic monomers have the ability to form nanosheets. An analysis of the crystal structures of several N,N′-disubstituted diketopiperazines (DKPs), a simple model system, revealed that the preferred solid-state packing arrangement of the hydrophobic groups can directly inform the assembly of stable peptoid nanosheets.序列定义类肽（peptoid）聚合物的结构与其组装为明确纳米结构的能力之间的关联，对于构建具备复杂功能的新型仿生平台具有重要意义。本研究对标准纳米片形成类肽序列中的疏水N-(2-苯乙基)甘氨酸（Npe）单体进行修饰，旨在达成以下四个目标：（1）利用相对短链的类肽制备纳米片；（2）抑制本体溶液中类肽的聚集行为；（3）通过强化疏水核内的堆积相互作用提升纳米片稳定性；（4）制备具有非芳香族疏水核的纳米片。对单个纳米片的荧光与光学显微镜观测结果显示，部分疏水核修饰具有良好耐受性，而另一些修饰则会导致纳米片不稳定、发生聚集，甚至阻碍组装过程。尤为关键的是，本研究证实Npe芳香环的间位与对位取代具备良好耐受性，这为调控类肽纳米片的功能特性提供了重要机遇。此外，我们发现N-芳基甘氨酸单体会抑制纳米片形成，而支链脂肪族单体则可形成纳米片。针对N,N'-二取代二酮哌嗪（DKPs）这一简单模型体系的晶体结构分析表明，疏水基团优选的固态堆积排布可直接为稳定类肽纳米片的组装提供指导依据。