Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion  

作　　者：Yiming Tang Yifei Yao Guanghong Wei 唐一鸣;姚逸飞;韦广红(Department of Physics,State Key Laboratory of Surface Physics and Key Laboratory for Computational Physical Science(Ministry of Education),and Multiscale Research Institute of Complex Systems,Fudan University,Shanghai 200433,China)

机构地区：[1]Department of Physics,State Key Laboratory of Surface Physics and Key Laboratory for Computational Physical Science(Ministry of Education),and Multiscale Research Institute of Complex Systems,Fudan University,Shanghai 200433,China

出　　处：《Chinese Physics B》2020年第10期66-75,共10页中国物理B（英文版）

基　　金：Project supported by the Key Program of the National Key Research and Development Program of China (Grant No. 2016YFA0501702);the National Natural Science Foundation of China (Grant No. 11674065)。

摘　　要：Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the β-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2–H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2–H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.

关 键 词：prion protein V127 variant molecular dynamics simulations dynamic network analysis 

分 类 号：R373[医药卫生—病原生物学]