On-the-Fly Specifications of Reaction Coordinates in Parallel Cascade Selection Molecular Dynamics Accelerate Conformational Transitions of Proteins
On-the-Fly Specifications of Reaction Coordinates in Parallel Cascade Selection Molecular Dynamics Accelerate Conformational Transitions of Proteins
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DOI：
10.1021/acs.jctc.8b00264
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发表时间：
2018-06-01
影响因子：
5.5
通讯作者：
Shigeta, Asuteru
中科院分区：
文献类型：
--
作者：
Harada, Ryuhei;Shigeta, Asuteru
平行级联选择分子动力学（PaCS-MD）是一种有效的构象采样方法，用于生成一组连接给定反应物和产物的反应轨迹。在PaCS-MD中，通过参考一组反应坐标（RC）合理地选择与构象转变相关的初始结构，并从它们独立地启动短时分子动力学（MD）模拟。为了有效地执行PaCS-MD，规范的RC是必不可少的，但指定合理的RC通常是不平凡的。在本研究中，我们提出了在飞规格的RC作为一个扩展的PaCS-MD。在本方法中，如下先验地提供n种类型的RC作为候选：RC =（X-1，X-2，...，X-n），并且其中一个RC以周期依赖的方式指定，即在每个周期通过评估RC的梯度来搜索合理的RC，即具有最陡梯度的RC被认为是合理的RC，并且构象重构沿着它进行，促进给定蛋白质的构象转变。作为示范，扩展的PaCS-MD被应用于再现T4溶菌酶（T4 L）的开-闭构象转变。作为可能的RC的候选者，在RC的循环依赖性规格中采用了（1）均方根距离、（2）主坐标、（3）可及表面积、（4）回转半径和（5）端到端距离。通过实验证明，扩展的PaCS-MD成功地再现了T4 L从开放态到封闭态的构象转变。作为更复杂的实践，扩展的PaCS-MD有效地再现了二遍蛋白的二聚化过程，显示了本算法的高构象采样效率。与此相反，传统的PaCS-MD与一个固定的RC有时无法产生一组反应轨迹时，指定一个不合理的RC，即PaCS-MD的构象采样效率可能或多或少地依赖于指定的RC。从目前的演示来看，在飞规格的RC可能是有效的复制/预测一个给定的蛋白质的基本转变。
Parallel Cascade Selection Molecular Dynamics (PaCS-MD) is an efficient conformational sampling method for generating a set of reactive trajectories that connect a given reactant and a product. In PaCS-MD, initial structures relevant to conformational transitions are reasonably selected by referring to a set of reaction coordinates (RCs), and short-time molecular dynamics (MD) simulations are independently launched from them. To efficiently perform PaCS-MD, specifications of RCs are essential, but specifying reasonable RCs is generally nontrivial. In the present study, we propose on-the-fly specifications of RCs as an extended PaCS-MD. In the present method, n types of RCs are provided as candidates a priori as follows: RC = (X-1, X-2, ..., X-n), and one of the RCs is specified in a cycle-dependent manner, i.e. the reasonable RC is searched at every cycle by evaluating gradients of the RCs, i.e. RC with the steepest gradient for cycle is regarded as the reasonable RC, and conformational resampling proceeds along it, promoting conformational transition of a given protein. For a demonstration, the extended PaCS-MD was applied to reproduce the open-closed conformational transition of T4 lysozyme (T4L). As candidates of possible RCs, (1) root-mean square distance, (2) principal coordinates, (3) accessible surface area, (4) radius of gyration, and (5) end-to-end distance were adopted in the cycle-dependent specifications of RCs. Through the demonstration, the extended PaCS-MD successfully reproduced the conformational transition from the open to closed states of T4L. As a more complicated practice, a dimerization process of diubiquitin was efficiently reproduced with the extended PaCS-MD, showing the high conformational sampling efficiency of the present algorithm. In contrast, the conventional PaCS-MD with a fixed RC sometimes failed to generate a set of reactive trajectories when an unreasonable RC was specified, i.e. the conformational sampling efficiency of PaCS-MD might more or less depend on the specified RCs. Judging from the present demonstrations, on-the-fly specifications of RCs might be effective in reproducing/predicting essential transitions of a given protein.