Wu C W, Sanborn T J, Huang K, Zuckermann R N, Barron A E
Department of Chemical Engineering, Northwestern University, Evanston, Illinois 60208, USA.
J Am Chem Soc. 2001 Jul 18;123(28):6778-84. doi: 10.1021/ja003154n.
The achiral backbone of oligo-N-substituted glycines or "peptoids" lacks hydrogen-bond donors, effectively preventing formation of the regular, intrachain hydrogen bonds that stabilize peptide alpha-helical structures. Yet, when peptoids are N-substituted with alpha-chiral, aromatic side chains, oligomers with as few as five residues form stable, chiral, polyproline-like helices in either organic or aqueous solution. The adoption of chiral secondary structure in peptoid oligomers is primarily driven by the steric influence of these bulky, chiral side chains. Interestingly, peptoid helices of this class exhibit intense circular dichroism (CD) spectra that closely resemble those of peptide alpha-helices. Here, we have taken advantage of this distinctive spectroscopic signature to investigate sequence-related factors that favor and disfavor stable formation of peptoid helices of this class, through a comparison of more than 30 different heterooligomers with mixed chiral and achiral side chains. For this family of peptoids, we observe that a composition of at least 50% alpha-chiral, aromatic residues is necessary for the formation of stable helical structure in hexameric sequences. Moreover, both CD and 1H-13C HSQC NMR studies reveal that these short peptoid helices are stabilized by the placement of an alpha-chiral, aromatic residue on the carboxy terminus. Additional stabilization can be provided by the presence of an "aromatic face" on the helix, which can be patterned by positioning aromatic residues with three-fold periodicity in the sequence. Extending heterooligomer chain length beyond 12-15 residues minimizes the impact of the placement, but not the percentage, of alpha-chiral aromatic side chains on overall helical stability. In light of these new data, we discuss implications for the design of helical, biomimetic peptoids based on this structural motif.
寡聚-N-取代甘氨酸或“类肽”的非手性主链缺乏氢键供体，有效地阻止了稳定肽α-螺旋结构的规则链内氢键的形成。然而，当类肽被α-手性芳香侧链N-取代时，寡聚物即使只有五个残基，在有机或水溶液中也会形成稳定的、手性的、聚脯氨酸样螺旋。类肽寡聚物中手性二级结构的形成主要是由这些庞大的手性侧链的空间影响驱动的。有趣的是，这类类肽螺旋表现出强烈的圆二色性（CD）光谱，与肽α-螺旋的光谱非常相似。在这里，我们利用这种独特的光谱特征，通过比较30多种具有混合手性和非手性侧链的不同杂合寡聚物，研究了有利于和不利于这类类肽螺旋稳定形成的序列相关因素。对于这类类肽，我们观察到在六聚体序列中，至少50%的α-手性芳香残基组成对于形成稳定的螺旋结构是必要的。此外，CD和1H-13C HSQC NMR研究都表明，这些短类肽螺旋通过在羧基末端放置一个α-手性芳香残基而得到稳定。螺旋上“芳香面”的存在可以提供额外的稳定性，这可以通过在序列中以三重周期性排列芳香残基来实现。将杂合寡聚物链长延长到12 - 15个残基以上，会使α-手性芳香侧链的位置对整体螺旋稳定性的影响最小化，但不会使其百分比最小化。鉴于这些新数据，我们讨论了基于这种结构基序设计螺旋仿生类肽的意义。
