Sotriffer C A, Flader W, Winger R H, Rode B M, Liedl K R, Varga J M
Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain 52a, Innsbruck, A-6020, Austria.
Methods. 2000 Mar;20(3):280-91. doi: 10.1006/meth.1999.0922.
Many approaches to studying protein-ligand interactions by computational docking are currently available. Given the structures of a protein and a ligand, the ultimate goal of all docking methods is to predict the structure of the resulting complex. This requires a suitable representation of molecular structures and properties, search algorithms to efficiently scan the configuration space for favorable interaction geometries, and accurate scoring functions to evaluate and rank the generated orientations. For many of the available methods, tests on experimentally known antibody-antigen or antibody-hapten complexes have appeared in the literature. In addition, some of them have been used in predictive studies on antibody-ligand interactions to provide structural insights where adequate experimental information is missing. The AutoDock program is presented as example of a method for flexibly docking ligands to antibodies. Applying parameters of the second-generation AMBER force field, three antibody-hapten complexes (AN02, DB3, NC6.8) are used as new test cases to analyze the ability of the method to reproduce experimental findings. The X-ray structures could be reconstituted and the corresponding solutions were ranked with best energy score in all cases. Docking to the free instead of the complexed NC6.8 structure indicated the limits of the rigid protein treatment, although fairly good guesses about the location of the binding site and the contact residues could still be obtained if conformational flexibility was allowed at least in the ligand.
目前有许多通过计算对接来研究蛋白质 - 配体相互作用的方法。给定蛋白质和配体的结构，所有对接方法的最终目标是预测所得复合物的结构。这需要合适的分子结构和性质表示、搜索算法以有效扫描配置空间寻找有利的相互作用几何结构，以及准确的评分函数来评估和排列生成的取向。对于许多现有方法，关于实验已知的抗体 - 抗原或抗体 - 半抗原复合物的测试已出现在文献中。此外，其中一些方法已用于抗体 - 配体相互作用的预测研究，以在缺乏足够实验信息时提供结构见解。以AutoDock程序为例介绍一种将配体灵活对接至抗体的方法。应用第二代AMBER力场的参数，使用三种抗体 - 半抗原复合物（AN02、DB3、NC6.8）作为新的测试案例来分析该方法重现实验结果的能力。在所有情况下都可以重构X射线结构，并将相应的解决方案按最佳能量得分进行排序。对接至游离的而非复合的NC6.8结构表明了刚性蛋白质处理的局限性，不过如果至少允许配体具有构象灵活性，仍可以对结合位点的位置和接触残基做出相当不错的猜测。
