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@ARTICLE{Rossetti:201265,
      author       = {Rossetti, Giulia and Giachin, Gabriele and Legname,
                      Giuseppe and Carloni, Paolo},
      title        = {{S}tructural facets of disease-linked human prion protein
                      mutants: {A} molecular dynamic study},
      journal      = {Proteins},
      volume       = {78},
      number       = {16},
      issn         = {0887-3585},
      address      = {New York, NY},
      publisher    = {Wiley-Liss},
      reportid     = {FZJ-2015-03570},
      pages        = {3270 - 3280},
      year         = {2010},
      abstract     = {Prion propagation in transmissible spongiform
                      encephalopathies involves the conversion of the cellular
                      prion protein, PrPC, into the pathogenic conformer PrPSc.
                      Human familial forms of the disease are linked to specific
                      mutations in the PrP gene, PRNP, and include
                      Gerstmann-Sträussler-Scheinker syndrome (GSS), familial
                      Creutzfeldt-Jakob disease (fCJD), and fatal familial
                      insomnia. To gain insights into the molecular basis of these
                      disorders, we performed 200 ns of classical molecular
                      dynamic simulations in aqueous solution on wild type (WT)
                      human PrP (HuPrP), and on three HuPrP variants located in
                      the globular HuPrP domain: two pathological mutations,
                      HuPrP(Q212P) and HuPrP(E200K), linked to GSS and to fCJD
                      respectively, and one protective polymorphism, HuPrP(E219K)
                      (total time-scale simulated 800 ns). A comparison between
                      the predicted structural determinants of WT HuPrP and
                      HuPrP(E200K) with their NMR structures established the
                      accuracy of the methods used. Strikingly, the analyzed
                      disease-linked variants produced their major effect on the
                      α2-α3 region and the β2-α2 loop, regardless of the
                      mutation position. The conformational change of the latter
                      might affect the interactions with cellular partners in the
                      fibrillation process. The protocol proposed here represents
                      a powerful approach for reproducing the structural effects
                      of genetic mutations located in the globular domain of
                      HuPrP, such as the GSS-related HuPrP(Q212P) and the
                      protective polymorphism HuPrP(E219K).},
      cin          = {German Research School for Simulation Sciences (GRS) /
                      IAS-5},
      ddc          = {540},
      cid          = {I:(DE-Juel1)GRS-20100316 / I:(DE-Juel1)IAS-5-20120330},
      pnm          = {899 - ohne Topic (POF2-899)},
      pid          = {G:(DE-HGF)POF2-899},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000284046400003},
      doi          = {10.1002/prot.22834},
      url          = {https://juser.fz-juelich.de/record/201265},
}