Simulation of Polyglutamine Aggregation With An Intermediate Resolution Protein Model

Abstract

The pathological manifestation of nine hereditary neurodegenerative diseases including Huntington's disease is the presence within the brain of aggregates of disease-specific proteins that contain polyglutamine tracts longer than a critical length. 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 fibril-forming peptides using molecular-level computer simulation. A simplified model of polyglutamine, the protein that is known to form fibrils (ordered aggregates of proteins in beta-sheet conformations) in the brains of victims of Huntington's disease, has been 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 utilizes discontinuous potentials such as hard spheres and square wells in order to take advantage of discontinuous molecular dynamics (DMD), a fast simulation technique that is very computationally efficient. DMD is used to examine the folding and aggregation of systems of model polyglutamine peptides ranging in size from isolated peptides to 96 peptides. In our simulations we observe the spontaneous formation of aggregates and annular structures that are made up of beta sheets starting from random configurations of random coils. The effect of chain length on the behavior of our model peptides was examined by simulating the folding of isolated polyglutamine peptides 16, 32, and 48 residues long and the folding and aggregation of systems of twenty-four model polyglutamine peptides 16, 32, 36, 40, and 48 residues long. In our multi-peptide simulations we observed that the optimal temperature for the formation of beta sheets increases with chain length up to 36 glutamine residues but not beyond. 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.