@article{MiettinenKnechtMonticellietal.2012,
  author    = {Miettinen, Markus S. and Knecht, Volker and Monticelli, Luca and Ignatova, Zoya},
  title     = {Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations},
  series = {The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces \& biophysical chemistry},
  volume    = {116},
  journal   = {The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces \& biophysical chemistry},
  number    = {34},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {1520-6106},
  doi       = {10.1021/jp305065c},
  pages     = {10259 -- 10265},
  year      = {2012},
  abstract  = {Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.},
  language  = {en}
}