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@ARTICLE{Ilie:858896,
      author       = {Ilie, Ioana M. and Nayar, Divya and den Otter, Wouter K.
                      and van der Vegt, Nico F. A. and Briels, Willem},
      title        = {{I}ntrinsic {C}onformational {P}references and
                      {I}nteractions in α-{S}ynuclein {F}ibrils: {I}nsights from
                      {M}olecular {D}ynamics {S}imulations},
      journal      = {Journal of chemical theory and computation},
      volume       = {14},
      number       = {6},
      issn         = {1549-9626},
      address      = {Washington, DC},
      reportid     = {FZJ-2018-07732},
      pages        = {3298 - 3310},
      year         = {2018},
      abstract     = {Amyloid formation by the intrinsically disordered
                      α-synuclein protein is the hallmark of Parkinson’s
                      disease. We present atomistic Molecular Dynamics simulations
                      of the core of α-synuclein using enhanced sampling
                      techniques to describe the conformational and binding free
                      energy landscapes of fragments implicated in fibril
                      stabilization. The theoretical framework is derived to
                      combine the free energy profiles of the fragments into the
                      reaction free energy of a protein binding to a fibril. Our
                      study shows that individual fragments in solution have a
                      propensity toward attaining non-β conformations, indicating
                      that in a fibril β-strands are stabilized by interactions
                      with other strands. We show that most dimers of
                      hydrogen-bonded fragments are unstable in solution, while
                      hydrogen bonding stabilizes the collective binding of five
                      fragments to the end of a fibril. Hydrophobic effects make
                      further contributions to the stability of fibrils. This
                      study is the first of its kind where structural and binding
                      preferences of the five major fragments of the hydrophobic
                      core of α-synuclein have been investigated. This approach
                      improves sampling of intrinsically disordered proteins,
                      provides information on the binding mechanism between the
                      core sequences of α-synuclein, and enables the
                      parametrization of coarse grained models.},
      cin          = {ICS-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)ICS-3-20110106},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551)},
      pid          = {G:(DE-HGF)POF3-551},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29715424},
      UT           = {WOS:000435416200043},
      doi          = {10.1021/acs.jctc.8b00183},
      url          = {https://juser.fz-juelich.de/record/858896},
}