Yao Hui, Mihalek Ivana, Lichtarge Olivier
Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine,Houston, Texas 77030, USA.
Proteins. 2006 Oct 1;65(1):111-23. doi: 10.1002/prot.21101.
Protein functional sites are key targets for drug design and protein engineering, but their large-scale experimental characterization remains difficult. The evolutionary trace (ET) is a computational approach to this problem that has been useful in a variety of case studies, but its proteomic scale application is partially hindered because automated retrieval of input sequences from databases often includes some with errors that degrade functional site identification. To recognize and purge these sequences, this study introduces a novel and structure-free measure of ET quality called rank information (RI). It is shown that RI decreases in response to errors in sequences, alignments, or functional classifications. Conversely, an automated procedure to increase RI by selectively removing sequences improves functional site identification so as to nearly match manually curated traces in kinases and in a test set of 79 diverse proteins. Thus we conclude that RI partially reflects the evolutionary consistency of sequence, structure, and function. In practice, as the size of the proteome continues to grow exponentially, it provides a novel and structure-free measure of ET quality that increases its accuracy for large-scale automated annotation of protein functional sites.
蛋白质功能位点是药物设计和蛋白质工程的关键靶点，但其大规模实验表征仍然困难。进化踪迹（ET）是解决此问题的一种计算方法，已在各种案例研究中发挥作用，但其蛋白质组规模的应用受到部分阻碍，因为从数据库自动检索输入序列时通常会包含一些错误序列，这些错误会降低功能位点识别的准确性。为了识别和清除这些序列，本研究引入了一种名为秩信息（RI）的新颖且无结构的ET质量度量。结果表明，RI会随着序列、比对或功能分类中的错误而降低。相反，通过选择性去除序列来提高RI的自动化程序可改善功能位点识别，从而在激酶和一组79种不同蛋白质的测试集中几乎与手动整理的踪迹相匹配。因此我们得出结论，RI部分反映了序列、结构和功能的进化一致性。实际上，随着蛋白质组规模持续呈指数增长，它提供了一种新颖且无结构的ET质量度量，提高了其在蛋白质功能位点大规模自动注释中的准确性。
