Topological frustration and the folding of interleukin-1β
Topological frustration and the folding of interleukin-1β
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DOI：
10.1016/j.jmb.2005.11.074
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发表时间：
2006-03-31
影响因子：
5.6
通讯作者：
Onuchic, JN
中科院分区：
文献类型：
--
作者：
Gosavi, S;Chavez, LL;Onuchic, JN
细胞因子，白细胞介素-1 β (IL-1 β)，采用β -三叶折叠。众所周知，它的折叠速度比类似大小的蛋白质要慢得多，尽管它的接触顺序很低。蛋白质设计得很好，它们的折叠不受局部能量陷阱的支配。因此，仅编码折叠结构且能量不受挫折（go型）的蛋白质模型可以捕获折叠路径的本质。我们利用这种模型和分子动力学（MD）模拟研究了IL-1 β的折叠热力学。我们开发了一种改进的采样技术（一种改进的多规范方法）来克服缓慢折叠引起的采样问题。我们发现IL-1 β具有宽而高的自由能垒。此外，蛋白质折叠导致蛋白质内部一些天然接触沿折叠轨迹的中间展开和再折叠。这种“回溯”发生在屏障区域周围。像β -三叶草折叠这样的复杂折叠和像IL-1 β的β -凸起这样的功能环可以使蛋白质无法获得一些构型空间，并导致拓扑挫折。(c) 2005 Elsevier Ltd版权所有。
The cytokine, iriterleukin-1 beta (IL-1 beta), adopts a beta-trefoil fold. It is known to be much slower folding than similarly sized proteins, despite having a low contact order. Proteins are sufficiently well designed that their folding is not dominated by local energetic traps. Therefore, protein models that encode only the folded structure and are energetically unfrustrated (GO-type), can capture the essentials of the folding routes. We investigate the folding thermodynamics of IL-1 beta using such a model and molecular dynamics (MD) simulations. We develop an enhanced sampling technique (a modified multicanonical method) to overcome the sampling problem caused by the slow folding. We find that IL-1 beta has a broad and high free energy barrier. In addition, the protein fold causes intermediate unfolding and refolding of some native contacts within the protein along the folding trajectory. This "backtracking" occurs around the barrier region. Complex folds like the beta-trefoil fold and functional loops like the beta-bulge of IL-1 beta can make some of the configuration space unavailable to the protein and cause topological frustration. (c) 2005 Elsevier Ltd. All rights reserved.