Harada Ryuhei, Yoshino Ryunosuke, Nishizawa Hiroaki, Shigeta Yasuteru
Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan; Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tenodai, Tsukuba, Ibaraki, 305-8577, Japan.
J Mol Graph Model. 2019 Nov;92:94-99. doi: 10.1016/j.jmgm.2019.07.007. Epub 2019 Jul 16.
We propose a flexible docking simulation based on parallel cascade selection molecular dynamics (PaCS-MD) as a post-processing treatment after a rigid docking simulation. PaCS-MD has been proposed as an enhanced sampling method for generating structural transition pathways from a given reactant to a product. The PaCS-MD cycle consists of the following two steps: (1) selections of important initial structures and (2) their conformational resampling from the selected initial structures. By repeating the conformational resampling from the important initial structures, structural transitions from the reactant to the product are gradually promoted. In the present flexible docking simulation, decoys (protein complexes) are generated by the rigid docking simulation a priori and employed as products of PaCS-MD. Then PaCS-MD is applied to reproduce association processes to the decoys from a reactant (completely separated proteins). To judge whether PaCS-MD found the association processes or not, the root-mean-square deviation measured from decoy (RMSD) was defined and monitored during the PaCS-MD cycles. By checking the RMSD values, a set of decoys is screened as a non-near native protein complex. In more detail, PaCS-MD detects near native protein complexes from the generated decoys by imposing a threshold (cutoff) for RMSD, i.e. RMSD < cutoff. As a demonstration, the present flexible docking addressed dimerization processes of K48-linked ubiquitin dimer without a covalent bond between its monomers. Finally, PaCS-MD screened out non-near native protein complexes from decoys generated by a rigid docking simulation.
我们提出了一种基于并行级联选择分子动力学（PaCS-MD）的灵活对接模拟方法，作为刚性对接模拟后的后处理手段。PaCS-MD已被提出作为一种增强采样方法，用于生成从给定反应物到产物的结构转变途径。PaCS-MD循环由以下两个步骤组成：（1）选择重要的初始结构；（2）从选定的初始结构中对其构象进行重新采样。通过重复从重要初始结构进行构象重新采样，逐渐促进从反应物到产物的结构转变。在当前的灵活对接模拟中，诱饵（蛋白质复合物）由刚性对接模拟预先生成，并用作PaCS-MD的产物。然后应用PaCS-MD来重现从反应物（完全分离的蛋白质）到诱饵的缔合过程。为了判断PaCS-MD是否找到了缔合过程，定义并在PaCS-MD循环期间监测从诱饵测量的均方根偏差（RMSD）。通过检查RMSD值，筛选出一组作为非近天然蛋白质复合物的诱饵。更详细地说，PaCS-MD通过对RMSD施加阈值（截止值），即RMSD < 截止值，从生成的诱饵中检测近天然蛋白质复合物。作为一个示例，当前的灵活对接研究了K48连接的泛素二聚体的二聚化过程，其单体之间没有共价键。最后，PaCS-MD从刚性对接模拟生成的诱饵中筛选出非近天然蛋白质复合物。
