Conservation of binding properties in protein models.
Conservation of binding properties in protein models.
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DOI：
10.1016/j.csbj.2021.04.048
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发表时间：
2021
影响因子：
6
通讯作者：
Vajda S
中科院分区：
文献类型：
--
作者：
Egbert M;Porter KA;Ghani U;Kotelnikov S;Nguyen T;Ashizawa R;Kozakov D;Vajda S
我们研究了提交给第12轮蛋白质结构预测关键评估（CASP）实验的模型，以评估当目标蛋白质的x射线结构被其模型取代时，其结合特性的保守程度。为了探索小分子结合，我们在蛋白质周围生成了分子探针的分布——这些探针是不同大小、形状和极性的碎片大小的有机分子，并计算每个残基和探针之间的相互作用次数，从而得到我们称之为结合指纹的相互作用向量。两个指纹（一个是x射线结构，另一个是蛋白质模型）之间的相似性是通过计算两个向量之间的相关系数来确定的。由此产生的相关系数与CASP中建立的全局精度测量相关，并且这种关系产生了一个精度阈值，必须达到该阈值才能实现有意义的结合表面守恒。探针分子形成的簇在x射线结构和目标的合理精确模型中都能可靠地预测结合热点和配体结合位点，但可能需要模型集合来评估适当结合口袋的可用性。我们探索了配体与x射线结构中结合配体的少数目标的对接。通过将x射线结构和模型与复合物中的相互作用伙伴对接，可以获得更多的目标来评估模型再现蛋白质-蛋白质相互作用的能力。结果表明，这种应用比寻找小配体结合位点要困难得多，而且成功率很大程度上取决于潜在界面中的局部结构。特别是，在其他高度精确的模型中，预测柔性环的构象经常是不正确的，并且可能阻止预测正确的蛋白质-蛋白质相互作用。
We study the models submitted to round 12 of the Critical Assessment of protein Structure Prediction (CASP) experiment to assess how well the binding properties are conserved when the X-ray structures of the target proteins are replaced by their models. To explore small molecule binding we generate distributions of molecular probes – which are fragment-sized organic molecules of varying size, shape, and polarity – around the protein, and count the number of interactions between each residue and the probes, resulting in a vector of interactions we call a binding fingerprint. The similarity between two fingerprints, one for the X-ray structure and the other for a model of the protein, is determined by calculating the correlation coefficient between the two vectors. The resulting correlation coefficients are shown to correlate with global measures of accuracy established in CASP, and the relationship yields an accuracy threshold that has to be reached for meaningful binding surface conservation. The clusters formed by the probe molecules reliably predict binding hot spots and ligand binding sites in both X-ray structures and reasonably accurate models of the target, but ensembles of models may be needed for assessing the availability of proper binding pockets. We explored ligand docking to the few targets that had bound ligands in the X-ray structure. More targets were available to assess the ability of the models to reproduce protein–protein interactions by docking both the X-ray structures and models to their interaction partners in complexes. It was shown that this application is more difficult than finding small ligand binding sites, and the success rates heavily depend on the local structure in the potential interface. In particular, predicted conformations of flexible loops are frequently incorrect in otherwise highly accurate models, and may prevent predicting correct protein–protein interactions.
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DOI：
10.1126/science.aad8266
发表时间：
2016-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen Y;Clarke OB;Kim J;Stowe S;Kim YK;Assur Z;Cavalier M;Godoy-Ruiz R;von Alpen DC;Manzini C;Blaner WS;Frank J;Quadro L;Weber DJ;Shapiro L;Hendrickson WA;Mancia F
通讯作者：
Mancia F
DOI：
10.1073/pnas.062398499
发表时间：
2002-04-02
影响因子：
11.1
作者：
Dennis, S;Kortvelyesi, T;Vajda, S
通讯作者：
Vajda, S
影响因子：
2.9
作者：
Guzenko, Dmytro;Lafita, Aleix;Duarte, Jose M.
通讯作者：
Duarte, Jose M.
影响因子：
6.1
作者：
Hajduk, PJ;Meadows, RP;Fesik, SW
通讯作者：
Fesik, SW
影响因子：
5.6
作者：
Alekseenko A;Kotelnikov S;Ignatov M;Egbert M;Kholodov Y;Vajda S;Kozakov D
通讯作者：
Kozakov D