Multi-scale ensemble modeling of modular proteins with intrinsically disordered linker regions: application to p53.
Multi-scale ensemble modeling of modular proteins with intrinsically disordered linker regions: application to p53.
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DOI：
10.1016/j.bpj.2014.06.026
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
Tsuyoshi Terakawa;J. Higo;S. Takada
中科院分区：
文献类型：
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作者：
Tsuyoshi Terakawa;J. Higo;S. Takada
在真核生物蛋白质中，固有无序区（IDR）普遍存在，并且通常存在于模块蛋白质的功能结构域侧翼的连接区中，调节其功能。详细的结构集成建模的IDRs，我们提出了一个多尺度的方法，IDRs具有显着的长程有序的模块化蛋白质，并将其应用到真核生物转录因子p53作为一个例子。首先，我们进行了全原子（AA）分子动力学（MD）模拟明确溶剂化的p53连接器区域，没有实验限制条款，发现分数的连接器内的远程接触。其次，我们将此AA MD集成到粗粒度（CG）模型中，找到一组最佳的接触电位。优化的CG MD模拟再现了来自AA MD模拟的接触概率图。最后，我们进行了CG MD模拟的四聚体p53片段，包括核心结构域，接头，和四聚化结构域。使用所获得的合奏，我们理论上计算的小角X射线散射（SAXS）的配置文件的这个片段。得到的小角X射线衍射谱与实验结果吻合较好。我们还发现，需要在p53连接区的长距离接触复制实验SAXS配置文件。开发的框架中，我们计算的远程接触概率地图从AA MD模拟，并将其纳入CG模型可以应用到广泛的IDR。
In eukaryotic proteins, intrinsically disordered regions (IDRs) are ubiquitous and often exist in linker regions that flank the functional domains of modular proteins, regulating their functions. For detailed structural ensemble modeling of IDRs, we propose a multiscale method for IDRs that possess significant long-range order in modular proteins and apply it to the eukaryotic transcription factor p53 as an example. First, we performed all-atom (AA) molecular dynamics (MD) simulations of the explicitly solvated p53 linker region, without experimental restraint terms, finding fractional long-range contacts within the linker. Second, we fed this AA MD ensemble into a coarse-grained (CG) model, finding an optimal set of contact potentials. The optimized CG MD simulations reproduced the contact probability map from the AA MD simulations. Finally, we performed the CG MD simulation of the tetrameric p53 fragments including the core domains, the linker, and the tetramerization domain. Using the obtained ensemble, we theoretically calculated the small angle x-ray scattering (SAXS) profile of this fragment. The obtained SAXS profile agrees well with the experiment. We also found that the long-range contacts in the p53 linker region are required to reproduce the experimental SAXS profile. The developed framework in which we calculate the long-range contact probability map from the AA MD simulation and incorporate it to the CG model can be applied to broad range of IDRs.