Virtua Drug Ltd, Csalogany Street 4C Budapest, Hungary.
J Cheminform. 2009 Sep 11;1:15. doi: 10.1186/1758-2946-1-15.
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 A 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.
分子对接方法常用于预测配体与蛋白质的结合模式和能量。为了准确估计复合物的几何形状和结合能，计算部分电荷的适当方法至关重要。AutoDockTools 软件是最广泛使用的对接程序之一 AutoDock 4 的输入文件准备接口，它同时使用 Gasteiger 方法计算蛋白质和配体的部分电荷。然而，已经表明，通过使用量子化学方法可以实现更准确的部分电荷计算，从而实现更准确的对接。迄今为止，用于对接计算的量子化学部分电荷计算通常仅用于配体。新开发的 MOPAC2009 的 Mozyme 功能允许通过量子力学半经验方法快速计算蛋白质的部分电荷。因此，在当前研究中，可以研究半经验量子力学部分电荷计算对对接准确性的影响。
使用原始 AutoDock 评分函数研究了一组 53 个蛋白配体复合物，利用 Gasteiger 和 PM6 部分电荷计算方法研究了 AutoDock 4 的对接准确性。这使我们能够利用 AutoDock 4 软件比较部分电荷计算方法对接准确性的影响。我们的结果表明，当使用半经验 PM6 方法计算配体和蛋白质的部分电荷时，对接准确性在复合物几何形状方面显著提高（当第一个排名的对接结果复合物的 RMSD 在 2 A 以内时，将对接结果定义为准确）。在我们的研究过程中分析的 53 个复合物中，使用 PM6 部分电荷准确计算了 42 个复合物的几何形状，而使用 Gasteiger 电荷则仅准确计算了 28 个几何形状。结合亲和力的估计不受部分电荷计算方法的影响-需要开发新的 AutoDock 评分函数以进行更准确的结合亲和力预测。
我们的结果表明，使用 AutoDock 4 进行对接计算时，复合物几何形状的确定准确性大大提高，同时在配体和蛋白质上都使用量子化学部分电荷计算。
