Implicit flexibility in protein docking: Cross-docking and local refinement
Implicit flexibility in protein docking: Cross-docking and local refinement
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DOI：
10.1002/prot.21698
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发表时间：
2007-12-01
影响因子：
2.9
通讯作者：
Bates, Paul A.
中科院分区：
文献类型：
--
作者：
Krol, Marcin;Chaleil, Raphael A. G.;Bates, Paul A.
在之前的 CAPRI 轮（3-5）中，我们表明，使用 MD 生成的集合作为刚体对接算法的输入，提高了我们的成功率，特别是对于表现出大量诱导拟合的目标。在最近几轮（6-11）中，我们的交叉对接之后是对最小化后具有最低相互作用能量的解决方案子集进行简短的基于 MD 的局部细化。上述方法显示了目标 20 的可喜结果，我们能够为我们提交的模型之一恢复 30% 的本地联系人。事后进行的进一步测试表明，交叉对接方法产生了更接近天然（NN）的解决方案，但仅适用于结合后构象发生较大变化的目标。然而，在盲对接实验时，这些改进的解决方案没有被选择用于后续的细化，因为它们最小化后的相互作用能量与其他解决方案相比排名较差。这表明当前基于最小化结构的相互作用能的评分方案存在缺陷。细化 MD 模拟大大增加了 NN 对接解决方案的自然接触比例，但通常会恶化界面和配体 RMSD。进一步的分析表明，尽管 MD 模拟能够改善界面上的侧链堆积，从而增加天然接触的比例，但即使使用显式溶剂，它们也无法将 NN 结构的界面和配体主链 RMSD 分别改善到超过 1.5 和 3.5 埃。
In previous CAPRI rounds (3-5) we showed that using MD-generated ensembles, as inputs for a rigid-body docking algorithm, increased our success rate, especially for targets exhibiting substantial amounts of induced fit. In recent rounds (6-11), our cross-docking was followed by a short MD-based local refinement for the subset of solutions with the lowest interaction energies after minimization. The above approach showed promising results for target 20, where we were able to recover 30% Of native contacts for one of our submitted models. Further tests, performed a posteriori, revealed that cross-docking approach produces more near-native (NN) solutions but only for targets with large conformational changes upon binding. However, at the time of the blind docking experiment, these improved solutions were not chosen for the subsequent refinement, as their interaction energies after minimization ranked poorly compared with other solutions. This indicates deficiencies in the present scoring schemes that are based on interaction energies of minimized structures. Refinement MD simulations substantially increase the fraction of native contacts for NN docked solutions, but generally worsen interface and ligand RMSD. Further analysis shows that although MD simulations are able to improve sidechain packing across the interface, which results in an increased fraction of native contacts, they are not capable of improving interface and ligand backbone RMSD for NN structures beyond 1.5 and 3.5 angstrom, respectively, even if explicit solvent is used.