title: Influence of the pathogenic mutations T188K/R/A on the structural stability and misfolding of human prion protein: insight from molecular dynamics simulations.
abstract: BACKGROUND
  Prion diseases are associated with a conformational switch for PrP from PrP(C) to PrP(Sc). Many genetic mutations are linked with prion diseases, such as mutations T188K/R/A with fCJD.
  
  
  METHODS
  MD simulations for the WT PrP and its mutants were performed to explore the underlying dynamic effects of T188 mutations on human PrP. Although the globular domains are fairly conserved, the three mutations have diverse effects on the dynamics properties of PrP, including the shift of H1, the elongation of native β-sheet and the conversion of S2-H2 loop to a 3(10) helix.
  
  
  CONCLUSIONS
  Our present study indicates that the three mutants for PrP may undergo different pathogenic mechanisms and the realistic atomistic simulations can provide insights into the effects of disease-associated mutations on PrP dynamics and stability, which can enhance our understanding of how mutations induce the conversion from PrP(C) to PrP(Sc). General significance Our present study helps to understand the effects of T188K/R/A mutations on human PrP: despite the three pathogenic mutations almost do not alter the native structure of PrP, but perturb its stability. This instability may further modulate the oligomerization pathways and determine the features of the PrP(Sc) assemblies.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.forename: Lulu
authors.initials: L
authors.lastname: Ning
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011328:Prions / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012997:Solvents
chemical_list: D050505:Mutant Proteins; D011328:Prions; D012997:Solvents