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@ARTICLE{Khaled:1006994,
      author       = {Khaled, Mohammed and Strodel, Birgit and Sayyed-Ahmad,
                      Abdallah},
      title        = {{C}omparative molecular dynamics simulations of pathogenic
                      and non-pathogenic huntingtin protein monomers and dimers},
      journal      = {Frontiers in molecular biosciences},
      volume       = {10},
      issn         = {2296-889X},
      address      = {Lausanne},
      publisher    = {Frontiers},
      reportid     = {FZJ-2023-01933},
      pages        = {1143353},
      year         = {2023},
      abstract     = {Polyglutamine expansion at the N-terminus of the huntingtin
                      protein exon 1 (Htt-ex1) is closely associated with a number
                      of neurodegenerative diseases, which result from the
                      aggregation of the increased polyQ repeat. However, the
                      underlying structures and aggregation mechanism are still
                      poorly understood. We performed microsecond-long all-atom
                      molecular dynamics simulations to study the folding and
                      dimerization of Htt-ex1 (about 100 residues) with
                      non-pathogenic and pathogenic polyQ lengths, and uncovered
                      substantial differences. The non-pathogenic monomer adopts a
                      long α-helix that includes most of the polyQ residues,
                      which forms the interaction interface for dimerization, and
                      a PPII-turn-PPII motif in the proline-rich region. In the
                      pathogenic monomer, the polyQ region is disordered, leading
                      to compact structures with many intra-protein interactions
                      and the formation of short β-sheets. Dimerization can
                      proceed via different modes, where those involving the
                      N-terminal headpiece bury more hydrophobic residues and are
                      thus more stable. Moreover, in the pathogenic Htt-ex1 dimers
                      the proline-rich region interacts with the polyQ region,
                      which slows the formation of β-sheets.},
      cin          = {IBI-7},
      ddc          = {570},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {37101557},
      UT           = {WOS:000976593100001},
      doi          = {10.3389/fmolb.2023.1143353},
      url          = {https://juser.fz-juelich.de/record/1006994},
}