Dynamic heterogeneity in the folding/unfolding transitions of FiP35
Dynamic heterogeneity in the folding/unfolding transitions of FiP35
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DOI：
10.1063/1.4916641
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发表时间：
2015-04-07
影响因子：
4.4
通讯作者：
Saito, Shinji
中科院分区：
文献类型：
--
作者：
Mori, Toshifumi;Saito, Shinji
在过去的几十年里，分子动力学模拟已经成为研究蛋白质动力学的重要工具。原子模拟的数量级为微秒到毫秒变得可行，并用于研究国家的最先进的实验在原子细节。然而，分析高维长时间的轨迹数据仍然是一项具有挑战性的任务，有时会导致矛盾的结果取决于分析。为了揭示轨迹的动态方面，这里我们提出了一种简单的方法，其使用时间相关函数矩阵并应用于FiP35 WW域的折叠/展开轨迹[Shaw等人，Science 330，341（2010）]。该方法成功地表征了对应于折叠/展开过渡的最慢模式，并确定了指示FiP35不是初期下坡折叠器的自由能垒。转变动力学分析进一步揭示了折叠/展开转变是高度异质的，例如，转换路径时间变化大约100倍。我们确定了两个错误折叠的状态，并表明在折叠/展开过渡的动态异质性起源于被困在错误折叠和半折叠的中间状态，而不是由热噪声驱动的扩散的轨迹。目前的结果有助于调和的折叠机制的相互冲突的解释，并强调在折叠动力学的复杂性。这进一步激发了需要理解超越简单的自由能图片使用模拟和单分子实验的过渡动力学。(c)2015 AIP Publishing LLC.
Molecular dynamics simulations have become an important tool in studying protein dynamics over the last few decades. Atomistic simulations on the order of micro-to milliseconds are becoming feasible and are used to study the state-of-the-art experiments in atomistic detail. Yet, analyzing the high-dimensional-long-temporal trajectory data is still a challenging task and sometimes leads to contradictory results depending on the analyses. To reveal the dynamic aspect of the trajectory, here we propose a simple approach which uses a time correlation function matrix and apply to the folding/unfolding trajectory of FiP35 WW domain [Shaw et al., Science 330, 341 (2010)]. The approach successfully characterizes the slowest mode corresponding to the folding/unfolding transitions and determines the free energy barrier indicating that FiP35 is not an incipient downhill folder. The transition dynamics analysis further reveals that the folding/unfolding transition is highly heterogeneous, e.g., the transition path time varies by similar to 100 fold. We identify two misfolded states and show that the dynamic heterogeneity in the folding/unfolding transitions originates from the trajectory being trapped in the misfolded and half-folded intermediate states rather than the diffusion driven by a thermal noise. The current results help reconcile the conflicting interpretations of the folding mechanism and highlight the complexity in the folding dynamics. This further motivates the need to understand the transition dynamics beyond a simple free energy picture using simulations and single-molecule experiments. (c) 2015 AIP Publishing LLC.