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Molecular Dynamics Simulations Indicate a Possible Role of Parallel ß-Helices in Seeded Aggregation of Poly-Gln

Martina Stork ^*, Armin Giese , Hans A. Kretzschmar  and Paul Tavan ^*

^* Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, Ludwig-Maximilians-Universität, D–80538 Munich, Germany; and Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität, Munich, Germany

Correspondence: Address reprint requests to Paul Tavan, Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, LMU, Oettingenstrasse 67, D–80538 Munich, Germany. Tel.: 49-89-2180-9220; Fax: 49-89-2180-9202; E-mail: paul.tavan{at}physik.uni-muenchen.de.

The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington's or transmissible spongiform encephalopathies are unknown. Recently, x-ray diffraction patterns of poly-Gln fibers and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel ß-helices. To explore this intriguing concept, we study the stability of small ß-helices in aqueous solution by molecular dynamics simulations. In particular, for the Huntington aggregation nucleus, which is thought to be formed of poly-Gln polymers, we show that three-coiled ß-helices are unstable at the suggested circular geometries and stable at a triangular shape with 18 residues per coil. Moreover, we demonstrate that individually unstable two-coiled triangular poly-Gln ß-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of sequences occurring in native ß-helices leads us to the proposal of a revised model for the PrP^Sc aggregation nucleus.

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