Karasev Dmitry A, Veselovsky Alexander V, Oparina Nina Yu, Filimonov Dmitry A, Sobolev Boris N
Russian National Research Medical University, Moscow, Russia.
Laboratory of Structure-Function Based Drug Design, Institute of Biomedical Chemistry (IBMC), Moscow, Russia.
J Mol Recognit. 2016 Apr;29(4):159-69. doi: 10.1002/jmr.2515. Epub 2015 Nov 8.
The exchange of single amino acid residue in protein can substantially affect the specificity of molecular recognition. Many protein families can be divided into the groups based on specificity to recognized ligands. Prediction of group-discriminating residues within the certain family is extremely necessary for theoretical studies, enzyme engineering, drug design, and so on. The most existing methods use the multiple sequence alignment. They have the limitations in prediction accuracy due to the family sequence divergence and ligand-based grouping. We developed a new method SPrOS (Specificity Projection On Sequence) for estimating the specificity of residues to user-defined groups. SPrOS compares the sequence segments from the test protein and training proteins. Contrary to other segment-comparison approaches extracting the string motifs, SPrOS calculates the scores for single positions by the similarity of their surroundings. The method was evaluated on the simulated sequences and real protein families. The high-prediction accuracy was achieved for simulated sequences, in which SPrOS detected specific positions not predicted with the alignment-based method. For bacterial transcription factors (LacI/GalR) clearly divided into functional groups, the predicted specific residues corresponded to the published experimental data. In a more complicated case of protein kinases classified by inhibitor specificity, the positions predicted with high significance were located in ligand-binding areas. As the ligand specificity is not necessary coincided with phylogeny, evolutionary-coupled mutations could disturb the detection of ligand-specific residues. Excluding proximate homologs of the test protein kinase from the training set, we improved the prediction of the ligand-specific residues. The SPrOS is available at http://www.way2drug.com/spros/
蛋白质中单个氨基酸残基的交换可显著影响分子识别的特异性。许多蛋白质家族可根据对所识别配体的特异性分为不同的组。预测特定家族内的组区分残基对于理论研究、酶工程、药物设计等极为必要。现有的大多数方法使用多序列比对。由于家族序列差异和基于配体的分组，它们在预测准确性方面存在局限性。我们开发了一种新方法SPrOS（序列特异性投影）来估计残基对用户定义组的特异性。SPrOS比较测试蛋白质和训练蛋白质的序列片段。与其他提取字符串基序的片段比较方法不同，SPrOS通过其周围环境的相似性计算单个位置的得分。该方法在模拟序列和真实蛋白质家族上进行了评估。对于模拟序列，实现了高预测准确性，其中SPrOS检测到了基于比对方法未预测到的特定位置。对于明显分为功能组的细菌转录因子（LacI/GalR），预测的特定残基与已发表的实验数据一致。在按抑制剂特异性分类的蛋白激酶这一更为复杂的情况下，具有高度显著性预测的位置位于配体结合区域。由于配体特异性不一定与系统发育一致，进化偶联突变可能会干扰配体特异性残基的检测。从训练集中排除测试蛋白激酶的近缘同源物后，我们改进了配体特异性残基的预测。可通过http://www.way2drug.com/spros/获取SPrOS。
