Four-body scoring function for mutagenesis
Four-body scoring function for mutagenesis
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DOI：
10.1093/bioinformatics/btm481
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发表时间：
2007-11-15
期刊：
影响因子：
5.8
通讯作者：
Krishnamoorthy, Bala
中科院分区：
文献类型：
--
作者：
Deutsch, Chris;Krishnamoorthy, Bala
动机：需要一种高效且准确的计算方法来确定单残基和多残基突变对蛋白质稳定性和反应性的影响。理想情况下，这种方法应具有一致性且能广泛应用，即它应能在相同参数设置下应用于各种蛋白质，并对所有蛋白质都具有良好的预测能力。
结果：我们开发了一种基于德劳内三角剖分的四体评分函数，用于预测单残基和多残基突变对蛋白质稳定性和反应性的影响。我们在先前几项研究使用的单点突变集上测试了我们的评分函数。我们还从24种以上不同的出版物中收集了一组新的、多样的237个单残基和多残基突变。四体评分函数正确预测了210个突变体中的169个（80.5%）的稳定性变化，以及27个突变体中的17个（63%）的反应性变化。对于那些稳定性/反应性变化已量化（使用反应速率、温度等）的突变体，四体评分与它们的斯皮尔曼等级相关系数平均为0.67。我们还开发了一种筛选大量蛋白质突变体的有效方法，称为组合诱变。在一项研究中，在一台个人电脑上，在几个小时内筛选了冷休克核结合域蛋白1CSQ的6400万个突变体，该蛋白的六个残基被改变为所有可能的（20种）氨基酸，并且组合诱变正确地识别出了所有五个稳定突变体。
可用性：所有已评分的突变体列表以及作为本研究一部分开发的程序的可执行文件可从以下网页获取：http://www.wsu.edu/~kbala/Mutate.html
联系人：kbala@wsu.edu或bkrishna@math.wsu.edu
补充信息：补充数据可在《生物信息学》在线获取。
Motivation: There is a need for an efficient and accurate computational method to identify the effects of single- and multiple-residue mutations on the stability and reactivity of proteins. Such a method should ideally be consistent and yet applicable in a widespread manner, i.e. it should be applied to various proteins under the same parameter settings, and have good predictive power for all of them.Results: We develop a Delaunay tessellation-based four-body scoring function to predict the effects of single- and multiple-residue mutations on the stability and reactivity of proteins. We test our scoring function on sets of single-point mutations used by several previous studies. We also assemble a new, diverse set of 237 single- and multiple-residue mutations, from over 24 different publications. The four-body scoring function correctly predicted the changes to the stability of 169 out of 210 mutants (80.5), and the changes to the reactivity of 17 out of 27 mutants (63). For the mutants that had the changes in stabilityreactivity quantified (using reaction rates, temperatures, etc.), an average Spearman rank correlation coefficient of 0.67 was achieved with the four-body scores. We also develop an efficient method for screening huge numbers of mutants of a protein, called combinatorial mutagenesis. In one study, 64 million mutants of a cold-shock nucleus binding domain protein 1CSQ, with six of its residues being changed to all possible (20) amino acids, were screened within a few hours on a PC, and all five stabilizing mutants reported were correctly identified as stabilizing by combinatorial mutagenesis.Availability: All lists of mutants scored, and executables of programs developed as part of this study are available from this web page: http://www.wsu.edu/similar to kbala/Mutate.htmlContact: kbala@wsu.edu or bkrishna@math.wsu.eduSupplementary information: Supplementary data are available at Bioinformatics online.