Fuchs Angelika, Martin-Galiano Antonio J, Kalman Matan, Fleishman Sarel, Ben-Tal Nir, Frishman Dmitrij
Department of Genome Oriented Bioinformatics, Technische Universität München, Wissenschaftszentrum Weihenstephan, 85350 Freising, Germany.
Bioinformatics. 2007 Dec 15;23(24):3312-9. doi: 10.1093/bioinformatics/btm515.
The analysis of co-evolving residues has been exhaustively evaluated for the prediction of intramolecular amino acid contacts in soluble proteins. Although a variety of different methods for the detection of these co-evolving residues have been developed, the fraction of correctly predicted contacts remained insufficient for their reliable application in the construction of structural models. Membrane proteins, which constitute between one-fourth and one-third of all proteins in an organism, were only considered in few individual case studies.
We present the first general study of correlated mutations in alpha-helical membrane proteins. Using seven different prediction algorithms, we extracted co-evolving residues for 14 membrane proteins having a solved 3D structure. On average, distances between correlated pairs of residues lying on different transmembrane segments were found to be significantly smaller compared to a random prediction. Covariation of residues was frequently found in direct sequence neighborhood to helix-helix contacts. Based on the results obtained from individual prediction methods, we constructed a consensus prediction for every protein in the dataset that combines obtained correlations from different prediction algorithms and simultaneously removes likely false positives. Using this consensus prediction, 53% of all predicted residue pairs were found within one helix turn of an observed helix-helix contact. Based on the combination of co-evolving residues detected with the four best prediction algorithms, interacting helices could be predicted with a specificity of 83% and sensitivity of 42%.
对共同进化残基的分析已被详尽评估，用于预测可溶性蛋白质中的分子内氨基酸接触。尽管已开发出多种不同方法来检测这些共同进化残基，但正确预测接触的比例仍不足以在构建结构模型中可靠应用。膜蛋白占生物体中所有蛋白质的四分之一到三分之一，仅在少数个别案例研究中被考虑。
我们首次对α螺旋膜蛋白中的相关突变进行了全面研究。使用七种不同的预测算法，我们为14种已解析三维结构的膜蛋白提取了共同进化残基。平均而言，与随机预测相比，位于不同跨膜片段上的相关残基对之间的距离明显更小。残基的共变经常出现在螺旋-螺旋接触的直接序列邻域中。基于从各个预测方法获得的结果，我们为数据集中的每个蛋白质构建了一个共识预测，该预测结合了从不同预测算法获得的相关性，并同时去除可能的假阳性。使用这种共识预测，发现所有预测的残基对中有53%位于观察到的螺旋-螺旋接触的一个螺旋旋转范围内。基于用四种最佳预测算法检测到的共同进化残基的组合，可以以83%的特异性和42%的灵敏度预测相互作用的螺旋。
