Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.
Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.
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DOI：
10.1021/acs.jcim.0c01207
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发表时间：
2021-04-26
影响因子：
5.6
通讯作者：
Senderowitz, Hanoch
中科院分区：
文献类型：
--
作者：
Bahia, Malkeet Singh;Khazanov, Netaly;Zhou, Qingxian;Yang, Zhengrong;Wang, Chi;Hong, Jeong S.;Rab, Andras;Sorscher, Eric J.;Brouillette, Christie G.;Hunt, John F.;Senderowitz, Hanoch
囊性纤维化 (CF) 是由囊性纤维化跨膜电导调节器 (CFTR) 氯离子通道突变引起的。 CFTR 由两个跨膜结构域、两个胞质核苷酸结合结构域（NBD1 和 NBD2）和一个很大程度上非结构化的 R 结构域组成。 NBD 中存在多种导致 CF 的突变，其中一些突变已知会损害这些结构域的稳定性。因此，预测突变对 CFTR 胞质结构域稳定性的影响并阐明突变发挥作用的机制的能力对于 CF 研究非常重要。考虑到这一点，我们使用 15 种不同的算法预测了 NBD1 和 NBD2 中 59 个突变对结构域稳定性的影响，并使用多个指标与实验数据进行比较来评估其性能，包括正确分类率 (CCR)、实验值和计算预测值之间计算的平方皮尔逊相关性 () 和斯皮尔曼相关性 ()。总体而言，FoldX 和 Rosetta 获得了最佳结果。对于 NBD1（35 个突变），FoldX 提供的 和 值分别为 0.64 和 –0.71，正确分类率 (CCR) 为 86%。对于 NBD2（24 个突变），FoldX 、 和 CCR 分别为 0.51、–0.73 和 75%。将 Rosetta 高分辨率协议 (Rosetta_hrp) 应用到 NBD1 上，得到 和 CCR 分别为 0.64、–0.75 和 69%，对于 NBD2，得到 和 CCR 分别为 0.29、–0.27 和 50%。 Rosetta 的低分辨率协议 (Rosetta_lrp) 的相应数字为 NBD1 = 0.47, = -0.69, CCR= 69%，NBD2 = 0.27, = -0.24, CCR = 63%。对于 NBD1，两种算法都表明不稳定突变会遭受不稳定 vdW 冲突的影响，而稳定突变则受益于有利的氢键相互作用。使用多数投票或全部投票尝试了两种基于 FoldX、Rosetta_lpr 和 Rosetta_hpr 的三重共识方法。尽管数据集较小，但全体投票共识的表现优于单个预测因素。总之，我们的结果表明突变对 CFTR NBD 稳定性的影响可以在很大程度上预测。由于 NBD 对所有 ABC 转运蛋白来说都是常见的，因此这些结果可用于预测其他蛋白质中多种致病突变的作用和作用机制。
Cystic Fibrosis (CF) is caused by mutations to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. CFTR is composed of two membrane spanning domains, two cytosolic nucleotide-binding domains (NBD1 and NBD2) and a largely unstructured R-domain. Multiple CF-causing mutations reside in the NBDs and some are known to compromise the stability of these domains. The ability to predict the effect of mutations on the stability of the cytosolic domains of CFTR and to shed light on the mechanisms by which they exert their effect is therefore important in CF research. With this in mind, we have predicted the effect on domain stability of 59 mutations in NBD1 and NBD2 using 15 different algorithms and evaluated their performances via comparison to experimental data using several metrics including the correct classification rate (CCR), and the squared Pearson correlation () and Spearman’s correlation () calculated between the experimental values and the computationally predicted values. Overall, the best results were obtained with FoldX and Rosetta. For NBD1 (35 mutations), FoldX provided and values of 0.64 and –0.71, respectively, with an 86% correct classification rate (CCR). For NBD2 (24 mutations), FoldX , , and CCR were 0.51, –0.73 and 75%, respectively. Application of the Rosetta high-resolution protocol (Rosetta_hrp) to NBD1 yielded , and CCR of 0.64, –0.75, and 69%, respectively, and for NBD2, , and CCR of 0.29, –0.27 and 50%, respectively. The corresponding numbers for the Rosetta’s low-resolution protocol (Rosetta_lrp) were = 0.47, = −0.69, CCR= 69% for NBD1 and = 0.27, = −0.24, CCR = 63% for NBD2. For NBD1, both algorithms suggest that destabilizing mutations suffer from destabilizing vdW clashes whereas stabilizing mutations benefit from favourable H-bond interactions. Two triple consensus approaches based on FoldX, Rosetta_lpr and Rosetta_hpr were attempted using either majority voting or all voting. The all voting consensus outperformed the individual predictors, albeit on a smaller data set. In summary, our results suggest that the effect of mutations on the stability of CFTR’s NBDs could be largely predicted. Since NBDs are common to all ABC transporters, these results may find usage in predicting the effect and mechanism of action of multiple disease-causing mutations in other proteins.
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影响因子：
2.9
作者：
Norimatsu, Yohei;Ivetac, Anthony;Alexander, Christopher;Kirkham, John;O'Donnell, Nicolette;Dawson, David C.;Sansom, Mark S. P.
通讯作者：
Sansom, Mark S. P.
FireProt：热稳定多点突变体的基于能量和进化的计算设计。
影响因子：
4.3
作者：
Bednar D;Beerens K;Sebestova E;Bendl J;Khare S;Chaloupkova R;Prokop Z;Brezovsky J;Baker D;Damborsky J
通讯作者：
Damborsky J
单点突变对蛋白质稳定性的三态预测发生了变化。
影响因子：
3
作者：
Capriotti, Emidio;Fariselli, Piero;Rossi, Ivan;Casadio, Rita
通讯作者：
Casadio, Rita
影响因子：
5.6
作者：
Guerois, R;Nielsen, JE;Serrano, L
通讯作者：
Serrano, L
影响因子：
3.7
作者：
Rishishwar L;Varghese N;Tyagi E;Harvey SC;Jordan IK;McCarty NA
通讯作者：
McCarty NA