Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706-1322, USA.
J Org Chem. 2010 Sep 17;75(18):6068-78. doi: 10.1021/jo101075a.
The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the ω, ϕ, and ψ dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n→π*(C═O) interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turnlike and beyond, and will facilitate the continued development of well-folded peptoids.
设计能够模拟天然生物聚合物定义结构模体的折叠物的能力对于功能仿生分子的持续发展至关重要。肽缩醛或 N-取代甘氨酸的低聚物代表了一类多功能折叠物，能够折叠成定义的二级和三级结构。然而，由于对指导局部肽缩醛折叠的共价和非共价相互作用的理解不完整，离散折叠肽缩醛的合理设计仍然是一项具有挑战性的任务。我们发现，简单的肽缩醛单体模型系统允许有效地分离肽缩醛主链和侧链中的单个相互作用，并有助于研究这些相互作用在限制局部肽缩醛构象中的作用。在此，我们提出了对一组含有能够与肽缩醛主链形成氢键的 N-芳基侧链的肽缩醛单体和低聚物的分析。这些模型肽缩醛表现出明确的局部构象偏好，允许控制系统采用的 ω、ϕ 和 ψ 二面角。对肽缩醛单体的基础研究使非环肽缩醛反向转弯结构的设计和合成成为可能，其中用邻位氢键供体装备的 N-芳基侧链被假设在转弯的稳定中起关键作用。这种三聚体肽缩醛通过 X 射线晶体学和 2D NMR 光谱进行了表征，并显示出独特的非环肽缩醛反向转弯构象。对该转弯的进一步分析揭示了肽缩醛主链内的 n→π*(C═O)相互作用，这代表了这种类型的立体电子相互作用仅在多肽缩醛主链内发生的第一个报道实例。将能够形成氢键的 N-芳基侧链引入肽缩醛是直接的，并且完全与当前的固相肽缩醛合成方法兼容。因此，我们预计这些 N-芳基侧链的战略引入将促进能够采用离散结构模体的肽缩醛的构建，包括转弯结构和其他结构，并将促进折叠良好的肽缩醛的持续发展。
