Effects of the Pathogenic Mutation A117V and the Protective Mutation H111S on the Folding and Aggregation of PrP106-126: Insights from Replica Exchange Molecular Dynamics Simulations.
Effects of the Pathogenic Mutation A117V and the Protective Mutation H111S on the Folding and Aggregation of PrP106-126: Insights from Replica Exchange Molecular Dynamics Simulations.
复制标题
致病性突变 A117V 和保护性突变 H111S 对 PrP106-126 折叠和聚集的影响：复制品交换分子动力学模拟的见解。
DOI：
10.1371/journal.pone.0125899
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
Ning L;Pan D;Zhang Y;Wang S;Liu H;Yao X
Prion蛋白的106-126片段表现出与全长Prion相似的性质。实验表明，A117V突变增强了PrP106-126的聚集性，而H111S突变取消了组装。然而，PrP106-126在这两个突变后聚集行为发生变化的机制尚不完全清楚。本研究采用复制交换分子动力学方法对WT PrP106-126及其两个突变体A117V和H111S的构象集成进行了研究。结果表明，这三个种都是本质上无序的，但它们在形态上存在明显的差异。A117V突变体比WT突变体具有更高的形成β-发夹结构的倾向，而H111S突变体具有更高的螺旋结构群体。此外，A117V突变增加了PrP106-126的疏水溶剂可及表面积，H111S突变减少了疏水残基的暴露。结论：β-发夹结构的群体差异和疏水溶剂可及区的变化可能导致A117V和H111S突变株的不同聚集行为。了解这两个突变对PrP106-126聚集性产生相反影响的原因，对于进一步阐明聚集性的机制和设计抑制聚集性的抑制剂具有重要意义。
The fragment 106-126 of prion protein exhibits similar properties to full-length prion. Experiments have shown that the A117V mutation enhances the aggregation of PrP106-126, while the H111S mutation abolishes the assembly. However, the mechanism of the change in the aggregation behavior of PrP106-126 upon the two mutations is not fully understood. In this study, replica exchange molecular dynamics simulations were performed to investigate the conformational ensemble of the WT PrP106-126 and its two mutants A117V and H111S. The obtained results indicate that the three species are all intrinsically disordered but they have distinct morphological differences. The A117V mutant has a higher propensity to form β-hairpin structures than the WT, while the H111S mutant has a higher population of helical structures. Furthermore, the A117V mutation increases the hydrophobic solvent accessible surface areas of PrP106-126 and the H111S mutation reduces the exposure of hydrophobic residues. It can be concluded that the difference in populations of β-hairpin structures and the change of hydrophobic solvent accessible areas may induce the different aggregation behaviors of the A117V and the H111S mutated PrP106-126. Understanding why the two mutations have contrary effects on the aggregation of PrP106-126 is very meaningful for further elucidation of the mechanism underlying aggregation and design of inhibitor against aggregation process.
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DOI：
10.1073/pnas.2433563100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Kuwata, K;Matumoto, T;Roder, H
通讯作者：
Roder, H
影响因子：
3.7
作者：
Gill AC
通讯作者：
Gill AC
影响因子：
4.8
作者：
CHEN, SG;TEPLOW, DB;AUTILIOGAMBETTI, L
通讯作者：
AUTILIOGAMBETTI, L
影响因子：
15
作者：
Grabenauer, Megan;Wu, Chun;Bowers, Michael T.
通讯作者：
Bowers, Michael T.
影响因子：
1.7
作者：
BROWN, DR;HERMS, J;KRETZSCHMAR, HA
通讯作者：
KRETZSCHMAR, HA