Kinetics analysis of ubiquitin local fluctuations with Markov state modeling of the LE4PD normal modes
Kinetics analysis of ubiquitin local fluctuations with Markov state modeling of the LE4PD normal modes
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DOI：
10.1063/1.5123513
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发表时间：
2019-10-28
影响因子：
4.4
通讯作者：
Guenza, Marina G.
中科院分区：
文献类型：
--
作者：
Beyerle, Eric P.;Guenza, Marina G.
局部波动对于蛋白质结合和分子识别很重要，因为它们提供了可以通过结合选择机制捕获的构象状态。因此，局部波动的准确表征对于模拟导致蛋白质生物活性的动力学机制可能很重要。在本文中，我们研究了调节蛋白泛素的波动动力学，并提出了一种新的理论方法来模拟其波动。使用朗之万蛋白质动力学方程 (LE4PD) 可以对波动进行粗粒度、扩散、模式相关的描述。该方程将分子动力学模拟的蛋白质动力学分解为探索模式相关自由能表面的动力学路径。我们通过使用马尔可夫态模型对二维自由能表面中势垒穿越动力学进行建模来计算缓慢、高振幅波动的时间尺度。我们发现 LE4PD 预测泛素中三个重要结合区域的缓慢波动：C 末端尾部、LysI 1 环和 50 s 环。这些结果表明，LE4PD 可以提供有关波动在调节泛素生物活性的分子识别过程中的作用的有用信息。由 AIP Publishing 许可发布。
Local fluctuations are important for protein binding and molecular recognition because they provide conformational states that can be trapped through a selection mechanism of binding. Thus, an accurate characterization of local fluctuations may be important for modeling the kinetic mechanism that leads to the biological activity of a protein. In this paper, we study the fluctuation dynamics of the regulatory protein ubiquitin and propose a novel theoretical approach to model its fluctuations. A coarse-grained, diffusive, mode-dependent description of fluctuations is accomplished using the Langevin Equation for Protein Dynamics (LE4PD). This equation decomposes the dynamics of a protein, simulated by molecular dynamics, into dynamical pathways that explore mode-dependent free energy surfaces. We calculate the time scales of the slow, high-amplitude fluctuations by modeling the kinetics of barrier crossing in the two-dimensional free energy surfaces using Markov state modeling. We find that the LE4PD predicts slow fluctuations in three important binding regions in ubiquitin: the C-terminal tail, the LysI 1 loop, and the 50 s loop. These results suggest that the LE4PD can provide useful information on the role of fluctuations in the process of molecular recognition regulating the biological activity of ubiquitin. Published under license by AIP Publishing.