Polyglutamine Fibrils: New Insights into Antiparallel β-Sheet Conformational Preference and Side Chain Structure

Understanding the structure of polyglutamine (polyQ) amyloid-like fibril aggregates is crucial to gaining insights into the etiology of at least ten neurodegenerative disorders, including Huntington's disease. Here, we determine the structure of D(2)Q(10)K(2) (Q10) fibrils using ultraviolet resonance Raman (UVRR) spectroscopy and molecular dynamics (MD). Using UVRR, we determine the fibril peptide backbone Psi and glutamine (Gin) side chain chi(3) dihedral angles. We find that most of the fibril peptide bonds adopt antiparallel beta-sheet conformations; however, a small population of peptide bonds exist in parallel beta-sheet structures. Using MD, we simulate three different potential fibril structural models that consist of either beta-strands or beta-hairpins. Comparing the experimentally measured Psi and chi(3) angle distributions to those obtained from the MD simulated models, we conclude that the basic structural motif of Q10 fibrils is an extended beta-strand structure. Importantly, we determine from our MD simulations that Q10 fibril antiparallel beta-sheets are thermodynamically more stable than parallel beta-sheets. This accounts for why polyQ fibrils preferentially adopt antiparallel beta-sheet conformations instead of in-register parallel beta-sheets like most amyloidogenic peptides. In addition, we directly determine, for the first time, the structures of Gln side chains. Our structural data give new insights into the role that the Gln side chains play in the stabilization of polyQ fibrils. Finally, our work demonstrates the synergistic power and utility of combining UVRR measurements and MD modeling to determine the structure of amyloid-like fibrils.