De novo design of a monomeric helical β-peptide stabilized by electrostatic interactions
De novo design of a monomeric helical β-peptide stabilized by electrostatic interactions
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DOI：
10.1021/ja010438e
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发表时间：
2001-05-30
影响因子：
15
通讯作者：
DeGrado, WF
中科院分区：
文献类型：
--
作者：
Cheng, RP;DeGrado, WF
多肽和蛋白质的从头设计提供了一种方法来批判性地评估负责蛋白质折叠和功能的特征。1最近在这方面取得的成功表明，现在应该可以将这种方法扩展到设计具有明确三级结构和活性的非生物聚合物。事实上，对各种序列特异性聚合物的早期研究表明，设计具有明确二级结构和性质的序列特异性聚合物是可行的。特别是由β-氨基酸组成的多肽(β-肽)在分子设计方面具有特殊的前景；2，4，5-β-氨基酸可以通过R-氨基酸的同源以及其他路线合成，提供了方便和高度多样化的单体来源。此外，与由R-氨基酸组成的多肽一样，它们本质上是灵活的，但仍然通过整个序列中弱相互作用的协同累积而采用明确的二级结构。因此，β-肽为我们将对蛋白质结构和稳定性的理解扩展到折叠的非生物聚合物领域提供了一个很好的框架。L+2螺旋是合成β-肽(图1)、2、4、5中特别稳定和经常观察到的构象，在其整体尺寸上与R-螺旋合理相似。在有机溶剂中形成L+2螺旋的立体化学要求来自Seebach和Gellman小组的开创性研究。然而，仅有一类具有构象受限的环状氨基酸的β-肽在水中具有稳定的L+2-螺旋构象。4A，d这里，我们证明了无环β-氨基酸侧链之间的静电相互作用可以用来驱动水中L+2螺旋的形成。
The de novo design of peptides and proteins has provided an approach to critically assess the features that are responsible for the folding and function of proteins. 1 Recent successes in this endeavor suggest that it should now be possible to extend this approach to the design of nonbiological polymers with welldefined tertiary structures and activities. Indeed, early work with a variety of sequence-specific polymers has shown the feasibility of designing sequence-specific polymers with well-defined secondary structures and properties. 2-5 In particular, peptides composed of β-amino acids (β-peptides) hold particular promise for molecular design; 2, 4, 5 β-amino acids can be synthesized by homologation of R-amino acids as well as other routes providing a convenient and highly diverse source of monomers. 6 Further, like peptides composed of R-amino acids, they are intrinsically flexible, but nevertheless adopt well-defined secondary structures through the cooperative accrual of weak interactions throughout the sequence. 2, 4, 5 Thus, β-peptides provide an excellent framework for extending our understanding of protein structure and stabilization into the realm of folded, nonbiological polymers.The L+ 2 helix is a particularly stable and frequently observed conformation in synthetic β-peptides (Figure 1), 2, 4, 5 which is reasonably similar to the R-helix in its overall dimensions. The stereochemical requirements for the formation of L+ 2 helices in organic solvents have emerged from pioneering studies from the groups of Seebach and Gellman. 2, 4, 5 However, the design of β-peptides that adopt stable L+ 2-helical conformations in water has been observed only for a class of peptides with conformationally restricted cyclic amino acids. 4a, d Here, we demonstrate that electrostatic interactions between the side chains of acyclic β-amino acids can be used to drive the formation of L+ 2 helices in water.