Aggregation in the brain of
polyglutamine-containing
proteins is either a cause or an associated symptom of nine hereditary
neurodegenerative disorders including
Huntington's disease. The molecular level mechanisms by which these
proteins aggregate are still unclear. In an effort to shed light on this important phenomenon, we are investigating the aggregation of model
polyglutamine peptides using molecular-level computer simulation with a simplified model of
polyglutamine that we have developed. This model accounts for the most important types of intra- and inter-molecular interactions-hydrogen bonding and hydrophobic interactions-while allowing the folding process to be simulated in a reasonable time frame. The model is used to examine the folding of isolated
polyglutamine peptides 16, 32, and 48 residues long and the folding and aggregation of systems of 24 model
polyglutamine peptides 16, 24, 32, 36, 40, and 48 residues long. Although the isolated
polyglutamine peptides did form some alpha and beta backbone-backbone hydrogen bonds they did not have as many of these bonds as they would have if they had folded into a complete alpha helix or beta sheet. In one of the simulations on the isolated
polyglutamine peptide 48 residues long, we observed a structure that resembles a beta helix. In the multi-chain simulations we observed amorphous aggregates at low temperatures, ordered aggregates with significant beta sheet character at intermediate temperatures, and random coils at high temperatures. We have found that the temperature at which the model
peptides undergo the transition from amorphous aggregates to ordered aggregates and the temperature at which the model
peptides undergo the transition from ordered aggregates to random coils increase with increasing chain length. Our finding that the stability of the ordered aggregates increases as the
peptide chain length increases may help to explain the experimentally observed relation between
polyglutamine tract length and aggregation in vitro and
disease progression in vivo. We have also observed in our simulations that the optimal temperature for the formation of beta sheets increases with chain length up to 36
glutamine residues but not beyond. Equivalently, at fixed temperature we find a transition from a region dominated by random coils at chain lengths less than 36 to a region dominated by relatively ordered beta sheet structures at chain lengths greater than 36. Our finding of this critical chain length of 36
glutamine residues is interesting because a critical chain length of 37
glutamine residues has been observed experimentally.