Testing a flexible-receptor docking algorithm in a model binding site
Testing a flexible-receptor docking algorithm in a model binding site
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DOI：
10.1016/j.jmb.2004.02.015
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发表时间：
2004-04-09
影响因子：
5.6
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
Wei, BQ;Weaver, LH;Shoichet, BK
采样受体的灵活性对于数据库对接是具有挑战性的。我们考虑一种方法，将多个灵活的区域的结合位点独立，重组它们产生不同的离散构象。该算法与受体的自由度成线性比例而不是指数比例。首先评价了该方法鉴定T4溶菌酶（L99 A）疏水腔突变体的已知配体的能力。大约200，000个可用化学目录（ACD）分子对接到腔构象的集合。令人惊讶的是，从ACD中大量诱饵中富集已知配体比简单地对接到单独的载脂蛋白构象更差。大诱饵，容纳在较大的腔构象采样合奏，排名比已知的小配体。重新进行计算，考虑到形成较大空腔构象的成本的能量校正项。富集得到改善，高级大型和小型配体之间的平衡也得到改善。在第二个回顾性测试中，ACD对接胸苷酸合酶的构象集合。与针对单个酶构象的对接相比，灵活的受体对接方法改善了已知配体的富集。包括受体构象能量加权项进一步改善了富集。为了前瞻性地测试该方法，ACD数据库针对溶菌酶的另一个空腔突变体（L99 A/M102 Q）进行对接。总共有18个新的化合物预测绑定这个极性腔，并改变其构象进行了实验测试，14个被发现绑定。通过X射线晶体学测定了7个配体的结合结构。这些配体的预测几何结构都对应于观察到的几何结构，在0.7埃RMSD或更好。在所有7个复合物中观察到空腔的显著构象变化。在五个结构中，部分观察到的住宿被正确预测;在两个结构中，受体构象的变化是意料之外的，因此从来没有采样。这些结果表明，虽然采样受体的灵活性可能会导致新的配体，对接刚性结构时会错过，它也是重要的是要考虑受体的构象能。(C)2004 Elsevier Ltd.保留所有权利。
Sampling receptor flexibility is challenging for database docking. We consider a method that treats multiple flexible regions of the binding site independently, recombining them to generate different discrete conformations. This algorithm scales linearly rather than exponentially with the receptor's degrees of freedom. The method was first evaluated for its ability to identify known ligands of a hydrophobic cavity mutant of T4 lysozyme (L99A). Some 200,000 molecules of the Available Chemical Directory (ACD) were docked against an ensemble of cavity conformations. Surprisingly, the enrichment of known ligands from among a much larger number of decoys in the ACD was worse than simply docking to the apo conformation alone. Large decoys, accommodated in the larger cavity conformations sampled in the ensemble, were ranked better than known small ligands. The calculation was redone with an energy correction term that considered the cost of forming the larger cavity conformations. Enrichment improved, as did the balance between high-ranking large and small ligands. In a second retrospective test, the ACD was docked against a conformational ensemble of thymidylate synthase. Compared to docking against individual enzyme conformations, the flexible receptor docking approach improved enrichment of known ligands. Including a receptor conformational energy weighting term improved enrichment further. To test the method prospectively, the ACD database was docked against another cavity mutant of lysozyme (L99A/M102Q). A total of 18 new compounds predicted to bind this polar cavity and to change its conformation were tested experimentally; 14 were found to bind. The bound structures for seven ligands were determined by X-ray crystallography. The predicted geometries of these ligands all corresponded to the observed geometries to within 0.7 Angstrom RMSD or better. Significant conformational changes of the cavity were observed in all seven complexes. In five structures, part of the observed accommodations were correctly predicted; in two structures, the receptor conformational changes were unanticipated and thus never sampled. These results suggest that although sampling receptor flexibility can lead to novel ligands that would have been missed when docking a rigid structure, it is also important to consider receptor conformational energy. (C) 2004 Elsevier Ltd. All rights reserved.