Prediction of viable circular permutants using a graph theoretic approach
Prediction of viable circular permutants using a graph theoretic approach
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DOI：
10.1093/bioinformatics/btl095
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发表时间：
2006-06-01
期刊：
影响因子：
5.8
通讯作者：
Lappe, Michael
中科院分区：
文献类型：
--
作者：
Paszkiewicz, Konrad H.;Sternberg, Michael J. E.;Lappe, Michael
动机：近年来，图论描述已被应用于帮助分析一些复杂的生物系统。然而，这种方法才刚刚开始应用于检查蛋白质结构和残基之间的相互作用网络，并取得了有希望的结果。在这里，我们研究了一种称为接近度的图度量是否能够预测蛋白质可以分裂形成可行的圆形排列体的区域。环状置换体是研究折叠机制的有力实验工具，最近被用于设计分裂酶报告蛋白。结果：我们在二氢叶酸还原酶上进行了一系列广泛的实验，其中为序列中的每个氨基酸位置构建了环状置换，以及来自其他蛋白质研究的部分数据，从而测试了我们的方法。结果表明，接近性比溶剂接近性能正确识别出更多适合循环排列的残留物。这对设计成功的分裂酶具有潜在的意义，对蛋白质-蛋白质相互作用筛选方法的发展具有特别重要的意义，并为蛋白质折叠提供了新的视角。更一般地说，该方法说明了图论测度成功地封装了折叠过程中残基之间的各种长程和短程相互作用。
Motivation: In recent years graph-theoretic descriptions have been applied to aid the analysis of a number of complex biological systems. However, such an approach has only just begun to be applied to examine protein structures and the network of interactions between residues with promising results. Here we examine whether a graph measure known as closeness is capable of predicting regions where a protein can be split to form a viable circular permutant. Circular permutants are a powerful experimental tool to probe folding mechanisms and more recently have been used to design split enzyme reporter proteins.Results: We test our method on an extensive set of experiments carried out on dihydrofolate reductase in which circular permutants were constructed for every amino acid position in the sequence, together with partial data from studies on other proteins. Results show that closeness is capable of correctly identifying significantly more residues which are suitable for circular permutation than solvent accessibility. This has potential implications for the design of successful split enzymes having particular importance for the development of protein-protein interaction screening methods and offers new perspectives on protein folding. More generally, the method illustrates the success with which graph-theoretic measures encapsulate the variety of long and short range interactions between residues during the folding process.