Ensemble docking of multiple protein structures: Considering protein structural variations in molecular docking
Ensemble docking of multiple protein structures: Considering protein structural variations in molecular docking
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DOI：
10.1002/prot.21214
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发表时间：
2007-02-01
影响因子：
2.9
通讯作者：
Zou, Xiaoqin
中科院分区：
文献类型：
--
作者：
Huang, Sheng-You;Zou, Xiaoqin
在分子对接中结合蛋白质柔性的一种方法是使用由多个蛋白质结构组成的系综。将每个配体依次对接到大量蛋白质结构中在计算上太昂贵，以至于不能进行大规模的数据库筛选。在对接精度和计算效率之间实现良好的平衡是具有挑战性的。在这项工作中，我们已经开发出一种快速，新颖的对接算法，利用多个蛋白质结构，称为合奏对接，占蛋白质结构的变化。该算法可以同时将配体对接到蛋白质结构的系综中，并通过优化配体坐标和构象变量m来自动选择最适合配体的最佳蛋白质结构，其中m表示蛋白质系综中的第m个结构。在包含105个晶体结构和87个配体的10个蛋白质系综上验证了对接算法的结合模式和能量分数预测。如果考虑每个配体的前五个方向，以均方根偏差< 2.5埃为标准，成功率为93%，与顺序对接（通过重新排序将单个对接的分数合并到一个列表中）相当，并且明显优于单个刚性受体对接（平均75%）。在结合评分预测和虚拟数据库筛选的富集测试中也观察到类似的趋势。系综对接算法是计算效率高，与对接到一个单一的蛋白质结构的配体的计算时间相当。相比之下，顺序对接方法的计算时间随着系综中蛋白质结构的数量线性增加。使用更真实的系综进一步评估该算法，其中排除了抑制剂的相应结合蛋白质结构。结果表明，系综对接成功地预测了抑制剂的结合模式，并从一组具有相似化学性质的非抑制剂区分抑制剂。虽然在目前的工作中使用了多个实验结构，我们的算法可以很容易地应用到多个蛋白质构象产生的计算方法，并有助于提高效率的其他现有的多蛋白质结构（MPS）为基础的方法，以适应蛋白质的灵活性。
One approach to incorporate protein flexibility in molecular docking is the use of an ensemble consisting of multiple protein structures. Sequentially docking each ligand into a large number of protein structures is computationally too expensive to allow large-scale database screening. It is challenging to achieve a good balance between docking accuracy and computational efficiency. In this work, we have developed a fast, novel docking algorithm utilizing multiple protein structures, referred to as ensemble docking, to account for protein structural variations. The algorithm can simultaneously dock a ligand into an ensemble of protein structures and automatically select an optimal protein structure that best fits the ligand by optimizing both ligand coordinates and the conformational variable m, where m represents the m-th structure in the protein ensemble. The docking algorithm was validated on 10 protein ensembles containing 105 crystal structures and 87 ligands in terms of binding mode and energy score predictions. A success rate of 93% was obtained with the criterion of root-mean-square deviation < 2.5 angstrom if the top five orientations for each ligand were considered, comparable to that of sequential docking in which scores for individual docking are merged into one list by re-ranking, and significantly better than that of single rigid-receptor docking (75% on average). Similar trends were also observed in binding score predictions and enrichment tests of virtual database screening. The ensemble docking algorithm is computationally efficient, with a computational time comparable to that for docking a ligand into a single protein structure. In contrast, the computational time for the sequential docking method increases linearly with the number of protein structures in the ensemble. The algorithm was further evaluated using a more realistic ensemble in which the corresponding bound protein structures of inhibitors were excluded. The results show that ensemble docking successfully predicts the binding modes of the inhibitors, and discriminates the inhibitors from a set of noninhibitors with similar chemical properties. Although multiple experimental structures were used in the present work, our algorithm can be easily applied to multiple protein conformations generated by computational methods, and helps improve the efficiency of other existing multiple protein structure(MPS)-based methods to accommodate protein flexibility.