Local Interactions That Contribute Minimal Frustration Determine Foldability
Local Interactions That Contribute Minimal Frustration Determine Foldability
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影响最小化的局部交互决定了可折叠性
DOI：
10.1021/acs.jpcb.1c00364
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Ozkan, Sefika Banu
中科院分区：
文献类型：
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作者：
Zou, Taisong;Woodrum, Brian W.;Halloran, Nicholas;Campitelli, Paul;Bobkov, Andrey A.;Ghirlanda, Giovanna;Ozkan, Sefika Banu
早期的实验表明，编码在蛋白质序列中的进化信息（保守和共同进化）是必要的，足以指定蛋白质家族的折叠。然而，没有计算工作来量化这种进化信息对折叠过程的影响。在这里，我们探讨的作用，早期折叠步骤的序列设计使用协同进化和保护，通过计算和实验方法相结合。我们模拟了一系列天然和设计的WW结构域序列来分析早期局部接触的形成，发现由于不可折叠序列中的强非天然局部接触，N末端β-发夹转角不会正确形成。通过最大似然法，我们确定了5个在折叠中起关键作用的局部接触，这表明可以使用氨基酸对的一个小子集来解决"大海捞针"问题以设计可折叠序列。因此，使用在折叠的早期阶段形成的这五个局部接触的接触概率，我们建立了一个分类模型，该模型以81%的准确度预测WW序列的可折叠性。该分类模型用于重新设计由于挫折而不能折叠的WW结构域序列，并通过引入导致这些关键局部接触稳定的一些突变使它们可折叠。实验分析表明，一个重新设计的序列折叠，并结合到聚脯氨酸肽与天然WW结构域所观察到的类似的亲和力。总的来说，我们的分析表明，进化设计的序列不仅应该满足折叠稳定性，而且还应确保最低限度的挫折折叠景观。
Earlier experiments suggest that the evolutionary information (conservation and coevolution) encoded in protein sequences is necessary and sufficient to specify the fold of a protein family. However, there is no computational work to quantify the effect of such evolutionary information on the folding process. Here we explore the role of early folding steps for sequences designed using coevolution and conservation through a combination of computational and experimental methods. We simulated a repertoire of native and designed WW domain sequences to analyze early local contact formation and found that the N-terminal β-hairpin turn would not form correctly due to strong non-native local contacts in unfoldable sequences. Through a maximum likelihood approach, we identified five local contacts that play a critical role in folding, suggesting that a small subset of amino acid pairs can be used to solve the “needle in the haystack” problem to design foldable sequences. Thus, using the contact probability of those five local contacts that form during the early stage of folding, we built a classification model that predicts the foldability of a WW sequence with 81% accuracy. This classification model was used to redesign WW domain sequences that could not fold due to frustration and make them foldable by introducing a few mutations that led to the stabilization of these critical local contacts. The experimental analysis shows that a redesigned sequence folds and binds to polyproline peptides with a similar affinity as those observed for native WW domains. Overall, our analysis shows that evolutionary-designed sequences should not only satisfy the folding stability but also ensure a minimally frustrated folding landscape.