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@ARTICLE{Poojari:140002,
      author       = {Poojari, Chetan and Strodel, Birgit},
      title        = {{S}tability of {T}ransmembrane {A}myloid ß-{P}eptide and
                      {M}embrane {I}ntegrity {T}ested by {M}olecular {M}odeling of
                      {S}ite-{S}pecific {A}ß$_{42}$ {M}utations},
      journal      = {PLoS one},
      volume       = {8},
      number       = {11},
      issn         = {1932-6203},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {FZJ-2013-05969},
      pages        = {e78399},
      year         = {2013},
      abstract     = {Interactions of the amyloid β-protein (Aβ) with neuronal
                      cell membranes, leading to the disruption of membrane
                      integrity, are considered to play a key role in the
                      development of Alzheimer’s disease. Natural mutations in
                      Aβ42, such as the Arctic mutation (E22G) have been shown to
                      increase Aβ42 aggregation and neurotoxicity, leading to the
                      early-onset of Alzheimer’s disease. A correlation between
                      the propensity of Aβ42 to form protofibrils and its effect
                      on neuronal dysfunction and degeneration has been
                      established. Using rational mutagenesis of the Aβ42 peptide
                      it was further revealed that the aggregation of different
                      Aβ42 mutants in lipid membranes results in a variety of
                      polymorphic aggregates in a mutation dependent manner. The
                      mutant peptides also have a variable ability to disrupt
                      bilayer integrity. To further test the connection between
                      Aβ42 mutation and peptide–membrane interactions, we
                      perform molecular dynamics simulations of membrane-inserted
                      Aβ42 variants (wild-type and E22G, D23G, E22G/D23G,
                      K16M/K28M and K16M/E22G/D23G/K28M mutants) as β-sheet
                      monomers and tetramers. The effects of charged residues on
                      transmembrane Aβ42 stability and membrane integrity are
                      analyzed at atomistic level. We observe an increased
                      stability for the E22G Aβ42 peptide and a decreased
                      stability for D23G compared to wild-type Aβ42, while D23G
                      has the largest membrane-disruptive effect. These results
                      support the experimental observation that the altered
                      toxicity arising from mutations in Aβ is not only a result
                      of the altered aggregation propensity, but also originates
                      from modified Aβ interactions with neuronal membranes.},
      cin          = {ICS-6},
      ddc          = {500},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {452 - Structural Biology (POF2-452)},
      pid          = {G:(DE-HGF)POF2-452},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000327162900014},
      doi          = {10.1371/journal.pone.0078399},
      url          = {https://juser.fz-juelich.de/record/140002},
}