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

Lulu Ning, Dabo Pan, Yan Zhang, Shaopeng Wang, Huanxiang Liu, Xiaojun Yao

研究成果: Article同行評審

7 引文 斯高帕斯(Scopus)

摘要

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.

原文English
文章編號e0125899
期刊PLoS ONE
10
發行號5
DOIs
出版狀態Published - 20 5月 2015
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