### abstract ###
MISC Expansion of polyglutamine tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases.
MISC Disease age of onset is correlated with the polyQ insert length above a critical value of 35 40 glutamines.
MISC The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence.
CONT While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood.
AIMX 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 -helix.
OWNX This transition occurs selectively in peptides longer than 37 glutamines.
OWNX In the -helices observed in simulations, all residues adopt -strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 2 residues per turn.
OWNX We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel -hairpins in their ground state, in agreement with experiments.
OWNX The lower stability of mutant -helices explains their lower aggregation rates compared to wild type.
OWNX Our results provide a molecular mechanism for polyQ-mediated aggregation.
### introduction ###
MISC The appearance of polyglutamine -containing aggregates CITATION CITATION is a hallmark of disease progression in all diseases in which CAG-expansions occur in genes CITATION.
MISC Intranuclear inclusion bodies containing polyQ aggregates have been found in vitro CITATION, CITATION, in cell cultures, animal models, and affected patients CITATION, CITATION.
MISC The aggregates are known to have a characteristic amyloid topology CITATION.
MISC The inhibition of oligomerization by the azo-dye Congo red, or by the Hsp70/Hsp40 chaperone system, exerts marked protective effects in vivo and in vitro CITATION, CITATION.
MISC Aggregation and disease are observed if the number of glutamines in the expansion, n, exceeds a critical value, n C CITATION.
MISC The nearly universal existence of this criticality in all polyQ-related diseases suggests that when the polyQ insert length exceeds a critical value, a pathological change, largely independent of the host protein, occurs in the polyQ insert itself.
MISC Therefore, isolated polyQ peptides have been used as model systems for studying polyQ aggregation CITATION, CITATION, CITATION, and it is known that: The nuclear uptake of polyQ peptide aggregates prepared in vitro is cytotoxic in cell cultures CITATION, isolated polyQ peptides have in vitro aggregation properties similar to the corresponding full-length proteins containing the polyQ insert CITATION, CITATION, peptide aggregation follows a nucleated mechanism showing characteristic lag and growth phases CITATION, CITATION, and the glutamine tract-length dependence of the lag-time interval correlates well with the age of onset of disease CITATION.
MISC Peptides of subcritical lengths have long lag times of aggregation and a corresponding age of onset later than the typical life span of a person.
MISC Longer peptides have progressively smaller lag times of aggregation, and a correspondingly early age of onset of the disease CITATION .
MISC Unaggregated polyQ peptides form random coil structures, whereas aggregates are composed of amyloid-like -strands CITATION.
MISC The conversion of random coil to -strand occurs in an individual polyQ chain CITATION, and fibril formation occurs by addition of other polyQ chains to these monomeric -strand nuclei.
MISC Therefore, the conformational dynamics of an individual polyQ chain determines both its aggregation mechanism and the structure of the final aggregates.
CONT The details of the conformational dynamics of polyQ and the length dependence of the dynamics are not well understood CITATION .
