Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly
Interplay among side chain sequence, backbone composition, and residue rigidification in polypeptide folding and assembly
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DOI：
10.1073/pnas.0801135105
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发表时间：
2008-07-08
影响因子：
11.1
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Horne, W. Seth;Price, Joshua L.;Gellman, Samuel H.
多肽构象在多大程度上取决于侧链组成和序列已经被广泛研究，但对维持α -氨基酸主链的重要性知之甚少。在这里，我们研究了一系列具有骨干的肽，其特征是α和β氨基酸残基的不同重复模式，但侧链序列不变。在纯α -主链中，该序列与先前研究的肽GCN4-pLI相对应，形成非常稳定的四螺旋束四级结构。溶液物理表征和晶体结构测定表明，多种α / β肽骨架可以采用与a原型相似的序列编码的四级结构。β -残基掺入后，螺旋束稳定性下降；然而，四元结构的稳定性并不是β -残基含量的简单函数。我们发现循环约束的β -氨基酸残基可以稳定α / β -肽GCN4-pLI类似物的折叠，并恢复在没有环残基时主要展开的骨架的四级结构形成。我们的研究结果显示了一个令人惊讶的可塑性程度，在主链组成方面，可以体现在氨基酸侧链序列编码的结构信息。这些发现为设计模仿蛋白质结构和功能特性的非天然低聚物提供了一个框架。
The extent to which polypeptide conformation depends on side-chain composition and sequence has been widely studied, but less is known about the importance of maintaining an alpha-amino acid backbone. Here, we examine a series of peptides with backbones that feature different repeating patterns of alpha- and beta-amino acid residues but an invariant side-chain sequence. In the pure alpha-backbone, this sequence corresponds to the previously studied peptide GCN4-pLI, which forms a very stable four-helix bundle quaternary structure. Physical characterization in solution and crystallographic structure determination show that a variety of alpha/beta-peptide backbones can adopt sequence-encoded quaternary structures similar to that of the a prototype. There is a loss in helix bundle stability upon beta-residue incorporation; however, stability of the quaternary structure is not a simple function of beta-residue content. We find that cyclically constrained beta-amino acid residues can stabilize the folds of alpha/beta-peptide GCN4-pLI analogues and restore quaternary structure formation to backbones that are predominantly unfolded in the absence of cyclic residues. Our results show a surprising degree of plasticity in terms of the backbone compositions that can manifest the structural information encoded in a sequence of amino acid side chains. These findings offer a framework for the design of nonnatural oligomers that mimic the structural and functional properties of proteins.