Physics Department T38, Technical University Munich, James Franck Str. 1, 85748 Garching, Germany.
BMC Bioinformatics. 2012 Sep 11;13:228. doi: 10.1186/1471-2105-13-228.
Protein-DNA interactions are important for many cellular processes, however structural knowledge for a large fraction of known and putative complexes is still lacking. Computational docking methods aim at the prediction of complex architecture given detailed structures of its constituents. They are becoming an increasingly important tool in the field of macromolecular assemblies, complementing particularly demanding protein-nucleic acids X ray crystallography and providing means for the refinement and integration of low resolution data coming from rapidly advancing methods such as cryoelectron microscopy.
We present a new coarse-grained force field suitable for protein-DNA docking. The force field is an extension of previously developed parameter sets for protein-RNA and protein-protein interactions. The docking is based on potential energy minimization in translational and orientational degrees of freedom of the binding partners. It allows for fast and efficient systematic search for native-like complex geometry without any prior knowledge regarding binding site location.
We find that the force field gives very good results for bound docking. The quality of predictions in the case of unbound docking varies, depending on the level of structural deviation from bound geometries. We analyze the role of specific protein-DNA interactions on force field performance, both with respect to complex structure prediction, and the reproduction of experimental binding affinities. We find that such direct, specific interactions only partially contribute to protein-DNA recognition, indicating an important role of shape complementarity and sequence-dependent DNA internal energy, in line with the concept of indirect protein-DNA readout mechanism.
蛋白质与 DNA 的相互作用对许多细胞过程至关重要，然而，对于很大一部分已知和推测的复合物，其结构知识仍然缺乏。计算对接方法旨在根据其组成部分的详细结构预测复合物的结构。它们在大分子组装领域正成为越来越重要的工具，特别是补充了对蛋白质-核酸 X 射线晶体学要求苛刻的方法，并为快速发展的方法（如冷冻电子显微镜）提供了低分辨率数据的细化和整合手段。
我们提出了一种新的适用于蛋白质-DNA 对接的粗粒度力场。该力场是先前开发的蛋白质-RNA 和蛋白质-蛋白质相互作用参数集的扩展。对接是基于配体在平移和取向自由度上的势能最小化。它允许在没有关于结合位点位置的先验知识的情况下，快速有效地进行类似于天然的复合物几何形状的系统搜索。
我们发现该力场在结合对接中给出了非常好的结果。在非结合对接的情况下，预测的质量因结构偏离结合构象的程度而异。我们分析了特定的蛋白质-DNA 相互作用对力场性能的影响，包括对复合物结构预测和实验结合亲和力的重现。我们发现，这种直接的、特定的相互作用只部分有助于蛋白质-DNA 识别，表明形状互补和序列依赖性 DNA 内部能量的重要作用，与间接蛋白质-DNA 读出机制的概念一致。
