Lindahl Erik, Delarue Marc
Unité de Biochimie Structurale, URA 2185 du CNRS, Institut Pasteur 25 Rue du Dr Roux, F-75015 Paris, France.
Nucleic Acids Res. 2005 Aug 8;33(14):4496-506. doi: 10.1093/nar/gki730. Print 2005.
Prediction of structural changes resulting from complex formation, both in ligands and receptors, is an important and unsolved problem in structural biology. In this work, we use all-atom normal modes calculated with the Elastic Network Model as a basis set to model structural flexibility during formation of macromolecular complexes and refine the non-bonded intermolecular energy between the two partners (protein-ligand or protein-DNA) along 5-10 of the lowest frequency normal mode directions. The method handles motions unrelated to the docking transparently by first applying the modes that improve non-bonded energy most and optionally restraining amplitudes; in addition, the method can correct small errors in the ligand position when the first six rigid-body modes are switched on. For a test set of six protein receptors that show an open-to-close transition when binding small ligands, our refinement scheme reduces the protein coordinate cRMS by 0.3-3.2 A. For two test cases of DNA structures interacting with proteins, the program correctly refines the docked B-DNA starting form into the expected bent DNA, reducing the DNA cRMS from 8.4 to 4.8 A and from 8.7 to 5.4 A, respectively. A public web server implementation of the refinement method is available at http://lorentz.immstr.pasteur.fr.
预测配体和受体中因复合物形成而导致的结构变化，是结构生物学中一个重要且尚未解决的问题。在这项工作中，我们使用基于弹性网络模型计算的全原子正常模式作为基组，来模拟大分子复合物形成过程中的结构灵活性，并沿着5 - 10个最低频率正常模式方向优化两个伙伴（蛋白质 - 配体或蛋白质 - DNA）之间的非键合分子间能量。该方法通过首先应用最能改善非键合能量的模式并可选地限制振幅，透明地处理与对接无关的运动；此外，当开启前六个刚体模式时，该方法可以校正配体位置的小误差。对于一组六个蛋白质受体的测试集，当结合小配体时显示出从开放到关闭的转变，我们的优化方案将蛋白质坐标cRMS降低了0.3 - 3.2 Å。对于两个蛋白质与DNA结构相互作用的测试案例，该程序正确地将对接的B - DNA起始形式优化为预期的弯曲DNA，分别将DNA cRMS从8.4 Å降低到4.8 Å以及从8.7 Å降低到5.4 Å。该优化方法的公共网络服务器实现可在http://lorentz.immstr.pasteur.fr获取。
