Wang Chu, Bradley Philip, Baker David
Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
J Mol Biol. 2007 Oct 19;373(2):503-19. doi: 10.1016/j.jmb.2007.07.050. Epub 2007 Aug 2.
Computational protein-protein docking methods currently can create models with atomic accuracy for protein complexes provided that the conformational changes upon association are restricted to the side chains. However, it remains very challenging to account for backbone conformational changes during docking, and most current methods inherently keep monomer backbones rigid for algorithmic simplicity and computational efficiency. Here we present a reformulation of the Rosetta docking method that incorporates explicit backbone flexibility in protein-protein docking. The new method is based on a "fold-tree" representation of the molecular system, which seamlessly integrates internal torsional degrees of freedom and rigid-body degrees of freedom. Problems with internal flexible regions ranging from one or more loops or hinge regions to all of one or both partners can be readily treated using appropriately constructed fold trees. The explicit treatment of backbone flexibility improves both sampling in the vicinity of the native docked conformation and the energetic discrimination between near-native and incorrect models.
目前，计算蛋白质-蛋白质对接方法能够创建出原子精度的蛋白质复合物模型，前提是结合时的构象变化仅限于侧链。然而，对接过程中考虑主链构象变化仍然极具挑战性，并且为了算法的简单性和计算效率，大多数当前方法本质上都保持单体主链刚性。在此，我们提出了一种Rosetta对接方法的重新表述，该方法在蛋白质-蛋白质对接中纳入了明确的主链灵活性。新方法基于分子系统的“折叠树”表示，它无缝整合了内部扭转自由度和刚体自由度。使用适当构建的折叠树，可以轻松处理从一个或多个环或铰链区域到一个或两个伙伴的所有区域的内部柔性区域问题。对主链灵活性的明确处理既改善了天然对接构象附近的采样，也改善了近天然模型与错误模型之间的能量区分。
