A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)
A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)
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DOI：
10.1007/s10822-008-9188-5
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Abagyan, Ruben
中科院分区：
文献类型：
--
作者：
Bottegoni, Giovanni;Kufareva, Irina;Abagyan, Ruben
蛋白质结合位点在配体结合后经历配体特异性构象变化。然而，大多数对接方案依赖于受体的固定构象，或依赖于代表口袋变化的多种构象的先验知识，或依赖于配体的已知边界框。在这里，我们描述了一个一般的诱导适合对接协议，只需要一个初始的口袋构象，并确定最低分数的正确配体位置。我们扩大了以前使用的不同的“交叉对接”基准三十配体蛋白质对提取不同的晶体结构。该算法系统地扫描相邻的侧链对，用丙氨酸取代它们，并将配体对接到每个“缺口”版本的口袋。对所有对接位置进行评分，用原始侧链和柔性主链精制并重新评分。在方案的最佳版本中，残基对被丙氨酸取代，并且从每个“缺口”口袋中仅选择一个最佳评分构象用于改进。最佳SCARE（SCan丙氨酸和REFine）协议将接近天然构象（在2埃RMSD下）识别为最低等级，如果对接边界框由预测的口袋信封定义，则80%的对，如果边界框来自已知答案，则多达90%的对具有与大多数先前出版物中使用的5埃裕度相似的裕度。所提出的全自动算法需要约2小时，每个姿势的一个单一的处理器的时间，只需要一个口袋结构，没有先验知识的结合位点的位置。此外，构象保守的口袋的结果不恶化，由于口袋的可变性大幅增加。
Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor, or on the prior knowledge of multiple conformations representing the variation of the pocket, or on a known bounding box for the ligand. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. We expanded a previously used diverse "cross-docking" benchmark to thirty ligand-protein pairs extracted from different crystal structures. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each 'gapped' version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each 'gapped' pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2 angstrom RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with similar to 5 angstrom margin as used in most previous publications. The presented fully automated algorithm takes about 2 h per pose of a single processor time, requires only one pocket structure and no prior knowledge about the binding site location. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.