Exploring structural and thermodynamic stabilities of human prion protein pathogenic mutants D202N, E211Q and Q217R

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• 作者：Jingjing Guo^a ; Hui Ren^b ; Lulu Ning^a ; Huanxiang Liu^a ; ^b ; ^{hxliu@lzu.edu.cn} ; Xiaojun Yao^a ; ^{xjyao@lzu.edu.cn}
• 关键词：Familial prion diseases ; Molecular dynamics simulation ; Prion protein (PrP) ; D202N/E211Q/Q217R mutants ; MM&ndash ; GBSA method
• 刊名：Journal of Structural Biology
• 出版年：2012
• 期刊代码：92_10478477
• 类别：ph
• 出版时间：June, 2012
• 卷：178
• 期：3
• 页码：225-232
• 文件大小：1644 K

摘要

The central event in the pathogenesis of prion protein (PrP) is a profound conformational change from its 伪-helical (PrP^C) to its 尾-sheet-rich isoform (PrP^Sc). Many single amino acid mutations of PrP are associated with familial prion diseases, such as D202N, E211Q, and Q217R mutations located at the third native 伪-helix of human PrP. In order to explore the underlying structural and dynamic effects of these mutations, we performed all-atom molecular dynamics (MD) simulations for the wild-type (WT) PrP and its mutants. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP.