Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations
Identification and characterization of the unfolding transition state of chymotrypsin inhibitor 2 by molecular dynamics simulations
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DOI：
10.1006/jmbi.1996.0172
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发表时间：
1996-03-29
影响因子：
5.6
通讯作者：
Daggett, V
中科院分区：
文献类型：
--
作者：
Li, AJ;Daggett, V
利用分子动力学模拟研究了糜蛋白酶抑制剂2（CI2）在水中的温度诱导去折叠。一个模拟（2.2 ns）进行了详细分析，并进行了三个额外的模拟（每个大于或等于1 ns），以检查结果的一般性。在所有的模拟过程中观察到同时损失的二级和三级结构展开。对于每个模拟，基于蛋白质结构的构象分析沿着展开轨迹沿着鉴定展开的主要过渡状态。过渡状态具有显著减弱的疏水核心和破坏的二级结构。然而，过渡态的整体结构更接近天然态而不是展开态。疏水核心的破坏似乎是速率限制的。然而，在达到主要过渡态之前必须克服其他能量障碍。描述了一种方法来定量比较模拟的过渡态的结构与蛋白质工程实验的特点。所有四种过渡态模型与实验数据吻合良好（相关系数R = 0.80至0.93），所有四种模型的平均值给出了最佳相关性（R = 0.94）。这些模拟提供了第一个全面的原子水平的视图是什么展开过渡态的C12可能看起来像。(C)1996年学术出版社
Temperature-induced unfolding of chymotrypsin inhibitor 2 (CI2) in water has been investigated using molecular dynamics simulations. One simulation (2.2 ns) has been analyzed in detail and three additional simulations (each greater than or equal to 1 ns) were performed to check the generality of the results. Concurrent loss of secondary and tertiary structure during unfolding was observed in all the simulations. For each simulation, the major transition state of unfolding was identified based on conformational analysis of protein structures along the unfolding trajectory The transition state has a considerably weakened hydrophobic core and disrupted secondary structure. Nevertheless, the overall structure of the transition state is closer to the native state than to the unfolded state. The disruption of the hydrophobic core appears to be rate limiting. However, other energy barriers have to be overcome before reaching the major transition state. A method is described to quantitatively compare the structure of the simulated transition state with that characterized by protein engineering experiments. Good agreement with the experimental data is obtained for all four transition state models (the correlation coefficient R = 0.80 to 0.93) and the average over all four models gives the best correlation (R = 0.94). These simulations provide the first comprehensive atomic-level view of what the unfolding transition state of C12 may look like. (C) 1996 Academic Press Limited