Intrinsic flexibility of DNA has hampered the development of efficient protein-DNA docking methods. In this study we extend HADDOCK (High Ambiguity Driven DOCKing) [C. Dominguez, R. Boelens and A. M. J. J. Bonvin (2003) J. Am. Chem. Soc. 125, 1731-1737] to explicitly deal with DNA flexibility. HADDOCK uses non-structural experimental data to drive the docking during a rigid-body energy minimization, and semi-flexible and water refinement stages. The latter allow for flexibility of all DNA nucleotides and the residues of the protein at the predicted interface. We evaluated our approach on the monomeric repressor-DNA complexes formed by bacteriophage 434 Cro, the Escherichia coli Lac headpiece and bacteriophage P22 Arc. Starting from unbound proteins and canonical B-DNA we correctly predict the correct spatial disposition of the complexes and the specific conformation of the DNA in the published complexes. This information is subsequently used to generate a library of pre-bent and twisted DNA structures that served as input for a second docking round. The resulting top ranking solutions exhibit high similarity to the published complexes in terms of root mean square deviations, intermolecular contacts and DNA conformation. Our two-stage docking method is thus able to successfully predict protein-DNA complexes from unbound constituents using non-structural experimental data to drive the docking.

译文

:DNA的固有灵活性已阻碍了有效的蛋白质-DNA对接方法的发展。在这项研究中,我们扩展了HADDOCK(高歧义性驱动DOCKing)[C。 Dominguez,R.Boelens和A.M.J.J.Bonvin(2003)J.Am.化学Soc。 125,1731-1737]明确涉及DNA的灵活性。 HADDOCK使用非结构性实验数据来驱动刚体能量最小化,半柔性和水提纯阶段的对接。后者允许所有DNA核苷酸和蛋白质残基在预测界面处具有柔韧性。我们评估了由噬菌体434 Cro,大肠杆菌Lac头饰和噬菌体P22 Arc形成的单体阻遏物-DNA复合物的方法。从未结合的蛋白质和典型的B-DNA开始,我们正确地预测了复合物的正确空间分布以及已发布复合物中DNA的特定构象。该信息随后用于生成预先弯曲和扭曲的DNA结构的库,该库用作第二轮对接的输入。最终的顶级解决方案在均方根偏差,分子间接触和DNA构象方面与已发表的复合物具有高度相似性。因此,我们的两阶段对接方法能够使用非结构性实验数据来驱动对接,从而从未结合的成分中成功预测蛋白质-DNA复合物。

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