The key event in force-induced unfolding of titin's immunoglobulin domains
The key event in force-induced unfolding of titin's immunoglobulin domains
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DOI：
10.1016/s0006-3495(00)76273-4
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Schulten, K
中科院分区：
文献类型：
--
作者：
Lu, H;Schulten, K
力诱导的肌联蛋白免疫球蛋白结构域127解折叠的操纵分子动力学模拟导致在解折叠途径上在类似于14埃的延伸处发现显著的势能势垒，其保护结构域免受拉伸。先前的模拟表明，这种屏障是由于β链A'和G之间的六个链间氢键（H-键）的同时断裂，在此之前，链A和B之间的两到三个氢键断裂，后者导致解折叠中间体。模拟结果支持埃分辨率原子力显微镜数据。在这里，我们进行的H-键断裂的结构和能量分析。证实链A和B之间的H-键迅速断裂。然而，链A'和G之间H键的断裂需要水分子的波动来辅助。在纳秒模拟中，发现水分子反复与蛋白质骨架原子相互作用，削弱单个链间氢键，直到所有六个A '-G氢键在外部拉伸力的影响下同时断裂。只有当这些键被打破时，才会发生通用的解折叠，这涉及蛋白质核心的疏水相互作用，并且比关键事件对拉伸的抵抗力更弱。
Steered molecular dynamics simulation of force-induced titin immunoglobulin domain 127 unfolding led to the discovery of a significant potential energy barrier at an extension of similar to 14 Angstrom on the unfolding pathway that protects the domain against stretching. Previous simulations showed that this barrier is due to the concurrent breaking of six interstrand hydrogen bonds (H-bonds) between beta-strands A' and G that is preceded by the breaking of two to three hydrogen bonds between strands A and B, the latter leading to an unfolding intermediate. The simulation results are supported by Angstrom-resolution atomic force microscopy data. Here we perform a structural and energetic analysis of the H-bonds breaking. It is confirmed that H-bonds between strands A and B break rapidly. However, the breaking of the H-bond between strands A' and G needs to be assisted by fluctuations of water molecules. In nanosecond simulations, water molecules are found to repeatedly interact with the protein backbone atoms, weakening individual interstrand H-bonds until all six A'-G H-bonds break simultaneously under the influence of external stretching forces. Only when those bonds are broken can the generic unfolding take place, which involves hydrophobic interactions of the protein core and exerts weaker resistance against stretching than the key event.