Center for Computational Biology, University of Kansas, Lawrence, KS 66047, USA.
Department of Geology and Physics, University of Southern Indiana, Evansville, IN 47712, USA.
Comput Biol Chem. 2018 Jun;74:286-293. doi: 10.1016/j.compbiolchem.2018.03.027. Epub 2018 Apr 5.
DNA interacts with small molecules, from water to endogenous reactive oxygen and nitrogen species, environmental mutagens and carcinogens, and pharmaceutical anticancer molecules. Understanding and predicting the physical interactions of small molecules with DNA via docking is key not only for the comprehension of molecular-level events that lead to carcinogenesis and other diseases, but also for the rational design of drugs that target DNA. We recently validated AutoDock, a popular docking method that includes a physics-based scoring function and a Lamarckian Genetic Algorithm, for the prediction of small molecule geometries upon physical binding to DNA. In this work, we added a vibrational entropy term based on the docking frequency to the scoring function in order to improve the accuracy of the best (lowest) score geometry. We found that in four small molecule-DNA systems the inclusion of the vibrational entropy term decreased the root-mean-square-deviation from the experimental crystallographic structure. Including the entropy term also preserved the successful prediction of the binding geometry compared to the crystallographic structure for the rest of the small molecule-DNA systems. We also improved the method of creating clusters of docking geometries and emphasized the importance of the length of the search process for similar vibrational entropy terms.
DNA 与小分子相互作用，从小分子如水、内源性活性氧和氮物种、环境诱变剂和致癌剂，到抗癌药物分子。通过对接理解和预测小分子与 DNA 的物理相互作用不仅是理解导致癌变和其他疾病的分子水平事件的关键，也是设计靶向 DNA 的药物的关键。我们最近验证了 AutoDock，这是一种流行的对接方法，包括基于物理的评分函数和 Lamarckian 遗传算法，用于预测小分子在与 DNA 物理结合时的几何形状。在这项工作中，我们在评分函数中添加了一个基于对接频率的振动熵项，以提高最佳（最低）得分几何形状的准确性。我们发现，在四个小分子-DNA 系统中，包含振动熵项降低了均方根偏差从实验晶体结构。与小分子-DNA 系统的其余部分的晶体结构相比，包含熵项也保留了对结合几何形状的成功预测。我们还改进了创建对接构象簇的方法，并强调了搜索过程长度对类似振动熵项的重要性。
