NR ASUG
AU Stork,M.; Giese,A.; Kretzschmar,H.A.; Tavan,P.
TI Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln
QU Biophysical Journal 2005 Apr; 88(4): 2442-51
PT journal article
AB 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 beta-helices. To explore this intriguing concept, we study the stability of small beta-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 beta-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 beta-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of approximately 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of sequences occurring in native beta-helices leads us to the proposal of a revised model for the PrPsc aggregation nucleus.
MH Amino Acid Motifs; Amyloid/chemistry; Biophysics/*methods; Computer Simulation; Crystallography, X-Ray; Databases, Protein; Dimerization; Humans; Models, Molecular; Models, Statistical; Peptides/*chemistry; PrPsc Proteins/chemistry; Protein Binding; Protein Conformation; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Research Support, Non-U.S. Gov't; Time Factors; X-Ray Diffraction
AD Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, Ludwig-Maximilians-Universität, D-80538 Munich, Germany.
SP englisch
PO USA
EA pdf-Datei und Supplement