TY - JOUR T1 - Molecular Origin of Polyglutamine Aggregation in Neurodegenerative Diseases A1 - Khare, Sagar D A1 - Ding, Feng A1 - Gwanmesia, Kenneth N A1 - Dokholyan, Nikolay V Y1 - 2005/08/26 N2 - Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35–40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel β-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the β-helices observed in simulations, all residues adopt β-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 ± 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel β-hairpins in their ground state, in agreement with experiments. The lower stability of mutant β-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 1 IS - 3 UR - https://doi.org/10.1371/journal.pcbi.0010030 SP - e30 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.0010030 ER -