The 3D profile method for identifying fibril-forming segments of proteins
The 3D profile method for identifying fibril-forming segments of proteins
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DOI：
10.1073/pnas.0511295103
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发表时间：
2006-03-14
影响因子：
11.1
通讯作者：
Eisenberg, D
中科院分区：
文献类型：
--
作者：
Thompson, MJ;Sievers, SA;Eisenberg, D
基于肽NNQQNY形成的交叉β棘的晶体结构，我们开发了一种计算方法来识别那些本身可以形成淀粉样原纤维的淀粉样蛋白片段。该方法建立在实验的基础上，实验表明六肽足以形成淀粉样原纤维。感兴趣的蛋白质的每个六残基肽被映射到模板的集合，或3D轮廓，由肽NNQQNY的晶体结构产生，通过两个相互交错的β -片中的一个相对于另一个的小位移。利用ROSETTADESIGN软件对序列的每次映射能量进行评估，并将给定肽段与模板库的最低能量匹配作为推定预测。如果假定预测的能量低于阈值，则对纤维的形成进行预测。当使用保守能量阈值将形成原纤维的肽与不形成原纤维的肽分离时，该方法可以达到接近80%的精度，P值接近10（-12）。我们在淀粉样蛋白的一组原纤维形成片段中看到了积极预测的富集，并且我们用淀粉样蛋白研究中感兴趣的蛋白质的应用来说明该方法。
Based on the crystal structure of the cross-beta spine formed by the peptide NNQQNY, we have developed a computational approach for identifying those segments of amyloidogenic proteins that themselves can form amyloid-like fibrils. The approach builds on experiments showing that hexapeptides are sufficient for forming amyloid-like fibrils. Each six-residue peptide of a protein of interest is mapped onto an ensemble of templates, or 3D profile, generated from the crystal structure of the peptide NNQQNY by small displacements of one of the two intermeshed beta-sheets relative to the other. The energy of each mapping of a sequence to the profile is evaluated by using ROSETTADESIGN, and the lowest energy match for a given peptide to the template library is taken as the putative prediction. If the energy of the putative prediction is lower than a threshold value, a prediction of fibril formation is made. This method can reach an accuracy of approximate to 80% with a P value of approximate to 10(-12) when a conservative energy threshold is used to separate peptides that form fibrils from those that do not. We see enrichment for positive predictions in a set of fibril-forming segments of amyloid proteins, and we illustrate the method with applications to proteins of interest in amyloid research.