Structure and dynamics of de novo proteins from a designed superfamily of 4-helix bundles
Structure and dynamics of de novo proteins from a designed superfamily of 4-helix bundles
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DOI：
10.1110/ps.073377908
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发表时间：
2008-05-01
期刊：
影响因子：
8
通讯作者：
Hecht, Michael H.
中科院分区：
文献类型：
--
作者：
Go, Abigail;Kim, Seho;Hecht, Michael H.
从头蛋白质文库提供了一个机会，可以探索生物分子的结构和功能潜力，这些分子没有受到数十亿年进化选择的影响。考虑到序列空间的相似性，一个合理的文库设计方法可能比随机序列的随机采样产生更高比例的折叠和功能蛋白质。我们先前研究了通过疏水性和亲水性氨基酸的二元图案化进行文库设计的潜力。来自从头4-螺旋束的二元模式化文库的最稳定的蛋白质的结构先前已被解决，并显示与设计一致。然而，一种结构不能完全评估设计策略的潜力，也不能解释单个蛋白质稳定性的差异。为了更全面地探测库的质量，我们现在报告第二种蛋白质S-836的NMR结构。蛋白S-836被证明是一个4-螺旋束，与设计一致。两个解决结构之间的相似性加强了以前的证据，二进制模式可以编码稳定的，4-螺旋束。尽管这两种蛋白质具有全球相似性，但它们的核心以不同的紧密程度包装。填充和动力学之间的关系进行了探讨，使用无模型的方法，这表明，含有高频率的化学交换的区域符合较少包装的侧链。这些研究表明：（1）二元模式化可以驱动折叠成特定的拓扑结构，而无需明确设计残基-残基包装;（2）在二元模式化蛋白质的超家族中，单个蛋白质的结构和动力学受到疏水核心中残基的身份和包装的调节。
Libraries of de novo proteins provide an opportunity to explore the structural and functional potential of biological molecules that have not been biased by billions of years of evolutionary selection. Given the enormity of sequence space, a rational approach to library design is likely to yield a higher fraction of folded and functional proteins than a stochastic sampling of random sequences. We previously investigated the potential of library design by binary patterning of hydrophobic and hydrophilic amino acids. The structure of the most stable protein from a binary patterned library of de novo 4-helix bundles was solved previously and shown to be consistent with the design. One structure, however, cannot fully assess the potential of the design strategy, nor can it account for differences in the stabilities of individual proteins. To more fully probe the quality of the library, we now report the NMR structure of a second protein, S-836. Protein S-836 proved to be a 4-helix bundle, consistent with design. The similarity between the two solved structures reinforces previous evidence that binary patterning can encode stable, 4-helix bundles. Despite their global similarities, the two proteins have cores that are packed at different degrees of tightness. The relationship between packing and dynamics was probed using the Modelfree approach, which showed that regions containing a high frequency of chemical exchange coincide with less well-packed side chains. These studies show ( 1) that binary patterning can drive folding into a particular topology without the explicit design of residue-by-residue packing, and ( 2) that within a superfamily of binary patterned proteins, the structures and dynamics of individual proteins are modulated by the identity and packing of residues in the hydrophobic core.