Simple Models of Polyglutamine Aggregation

University Of California San Diego, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): I will use simulations to investigate the structural ensemble of polyglutamine, based on the model peptide system AC.D:QMArNI12, using simplified protein models to determine if increasing the polyglutamine length QN stabilizes about hairpin conformations. The first stage is to introduce polyglutamine QN into chymotrypsin inhibitor 2 to determine if experimental folding/stability perturbations can be reproduced by minimalist models and determine attraction parameters between glutamine residues. Having established this first step, the second stage will be made to determine if a beta-hairpin conformation is more stable in the monomeric state of Ac-D2QNA2-NH2 peptides as the polyglutamine length is increased. When experimental data is available, agreement between simulated structures of the Ac-D2QNA2-NH-12 peptides and experiments will be used to validate experimental parameters. The third stage is to determine whether the p-hairpin is a crucial state mediating early association events in polyglutamine aggregation. At each stage, the results will be compared to the results of collaborative single-molecule FRET experiments. These studies will address the hypothesis that preexisting beta-sheet structure is a prerequisite to association events in polyglutamine aggregation.