Molecular dynamics simulations indicate a possible role of parallel β-helices in seeded aggregation of poly-Gln

Abstract

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 β-helices. To explore this intriguing concept, we study the stability of small β-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 β-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 β-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 β-helices leads us to the proposal of a revised model for the PrPSc aggregation nucleus. © 2005 by the Biophysical Society.