Computational Alanine Scanning Mutagenesis: MM-PBSA vs TI
Computational Alanine Scanning Mutagenesis: MM-PBSA vs TI
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DOI：
10.1021/ct4000372
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发表时间：
2013-03-01
影响因子：
5.5
通讯作者：
Fernandes, P. A.
中科院分区：
文献类型：
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作者：
Martins, Silvia A.;Perez, Marta A. S.;Fernandes, P. A.
了解蛋白质-蛋白质关联并能够确定负责其关联的关键残基（热点）是具有巨大实际应用的关键问题，例如合理药物设计和蛋白质工程。存在多种计算方法来检测热点残基，但开发快速准确的定量丙氨酸扫描诱变（ASM）仍然是至关重要的。使用四种蛋白质-蛋白质复合物，我们比较了在我们组开发的标准计算ASM协议的变化，基于分子力学/泊松-玻尔兹曼表面积（MM-PBSA）方法，对热力学积分（TI），一个众所周知的和准确的，但计算昂贵的方法。为了比较两种方法的效率和准确性，我们计算了界面残基丙氨酸突变后的蛋白质-蛋白质结合自由能差（Delta Delta G（bind））。相对于实验Δ Δ G（结合）值，用TI获得的平均误差为1.53 kcal/mol，而ASM方案导致的平均误差为1.18 kcal/mol。结果表明，更快的ASM协议给出的结果在相同的精度水平的TI方法，但在一小部分所需的计算时间运行TI。因此，ASM协议是一个强大的和有效的替代蛋白质-蛋白质界面的系统评价，涉及数百个氨基酸残基的热点搜索。
Understanding protein-protein association and being able to determine the crucial residues responsible for their association (hot-spots) is a key issue with huge practical applications such as rational drug design and protein engineering. A variety of computational methods exist to detect hot-spots residues, but the development of a fast and accurate quantitative alanine scanning mutagenesis (ASM) continues to be crucial. Using four protein-protein complexes, we have compared a variation of the standard computational ASM protocol developed at our group, based on the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) approach, against Thermodynamic Integration (TI), a well-known and accurate but computationally expensive method. To compare the efficiency and the accuracy of the two methods, we have calculated the protein-protein binding free energy differences upon alanine mutation of interfacial residues (Delta Delta G(bind)). In relation to the experimental Delta Delta G(bind) values, the average error obtained with TI was 1.53 kcal/mol, while the ASM protocol resulted in an average error of 1.18 kcal/mol. The results demonstrate that the much faster ASM protocol gives results at the same level of accuracy as the TI method but at a fraction of the computational time required to run TI. This ASM protocol is therefore a strong and efficient alternative to the systematic evaluation of protein-protein interfaces, involving hundreds of amino acid residues in search of hot-spots.