Effects of chain length on the aggregation of model polyglutamine peptides: Molecular dynamics simulations

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2007-01, Vol.66 (1), p.96-109
• Main Authors: Marchut, Alexander J., Hall, Carol K.
• Format: Article
• Language: English
• Subjects: amyloid; Computer Simulation; Dimerization; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; intermediate resolution model; Models, Molecular; molecular dynamics; Peptides - chemistry; Peptides - metabolism; polyglutamine; protein aggregation; Protein Folding; Temperature
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.21132

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 α and β backbone–backbone hydrogen bonds they did not have as many of these bonds as they would have if they had folded into a complete α helix or β sheet. In one of the simulations on the isolated polyglutamine peptide 48 residues long, we observed a structure that resembles a β helix. In the multi‐chain simulations we observed amorphous aggregates at low temperatures, ordered aggregates with significant β 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 β 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 β sheet structures at chain lengths greater than 36. Our finding of this critical chain length of 36 glutamine residues i