Rarey M, Kramer B, Lengauer T, Klebe G
German National Research Center for Information Technology (GMD), Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, Germany.
J Mol Biol. 1996 Aug 23;261(3):470-89. doi: 10.1006/jmbi.1996.0477.
We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 A rms deviation. It is almost always found among the highest-ranking conformations computed.
我们提出了一种将有机配体对接至蛋白质结合位点的自动方法。该方法可用于特定蛋白质配体的设计过程。它将对接分子物理化学性质的合适模型与有效采样配体构象空间的方法相结合。如果配体是柔性的，它可以采用多种不同的构象。构象空间中的每个这样的最小值都代表了配体在复合状态下构象的潜在候选者。我们的对接方法基于离散模型对配体的构象空间进行采样，并使用树搜索技术将配体逐步放置到活性位点。为了将配体的第一个片段放置到蛋白质中，我们使用了源自计算机视觉的哈希技术。增量构建算法基于贪婪策略，并结合了用于重叠检测和新相互作用搜索的有效方法。我们给出了19个复合物的结果，其结合几何结构已通过晶体学确定。在当前工作站上，所有考虑的配体对接最多只需三分钟。配体的实验观察到的结合模式以0.5至1.2埃的均方根偏差被重现。它几乎总是在计算出的最高排名构象中被发现。
