Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock.
Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock.
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DOI：
10.1186/1758-2946-1-15
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发表时间：
2009-09-11
影响因子：
8.6
通讯作者：
Hazai E
中科院分区：
文献类型：
--
作者：
Bikadi Z;Hazai E
分子对接方法通常用于预测配体与蛋白质的结合方式和能量。对于精确的复杂几何构型和结合能的估计，一个合适的计算部分电荷的方法是必不可少的。AutoDockTools软件是为最广泛使用的对接程序之一AutoDock 4准备输入文件的界面，它利用Gasteiger部分电荷计算方法计算蛋白质和配体电荷。然而，已经证明，使用量子化学方法可以实现更准确的部分电荷计算--因此，可以实现更准确的对接。在对接计算中，量子化学部分电荷计算是一种常规的计算方法，到目前为止只用于配体。MOPAC2009的新开发的Mozyme功能允许用量子力学半经验方法快速计算蛋白质的部分电荷。因此，在目前的研究中，可以研究半经验量子力学部分电荷计算对对接精度的影响。采用Gasteiger和PM6部分电荷计算方法，研究了AutoDock 4在一组53个蛋白质配体复合体上的对接精度。这使我们能够利用AutoDock 4软件比较部分电荷计算方法对对接精度的影响。我们的结果表明，用半经验PM6方法计算配体和蛋白质的部分电荷时，复杂几何结构的对接精度(对接结果的RMSD定义为一阶对接结果络合物的RMSD与实验确定的X射线结构的RMSD在2ä以内时定义为准确)显著提高。在我们研究过程中分析的53个络合物中，42个络合物的几何构型使用PM6部分电荷得到了准确的计算，而使用Gasteiger电荷只得到了28个精确的几何构型。结合亲和力的估计不受部分电荷计算方法的影响-为了更准确地预测结合亲和力，需要为AutoDock开发一个新的评分函数。我们的结果表明，使用AutoDock 4进行对接计算时，通过对配体和蛋白质进行量子化学部分电荷计算，可以大大提高确定复杂几何构型的精度。
Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated. The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method. Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed. Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.