title: Structural determinants of polyglutamine protofibrils and crystallites.
abstract: Nine inherited neurodegenerative diseases are associated with the expansion of the CAG codon. Once the translated polyglutamine expansion becomes longer than ~36 residues, it triggers the formation of intraneural protein aggregates that often display the signature of cross-β amyloid fibrils. Here, we use fully atomistic molecular dynamics simulations to probe the structural stability and conformational dynamics of both previously proposed and new polyglutamine aggregate models. We test the relative stability of parallel and antiparallel β sheets, and characterize possible steric interfaces between neighboring sheets and the effects of different alignments of the side-chain carboxamide dipoles. Results indicate that (i) different initial oligomer structures converge to crystals consistent with available diffraction data, after undergoing cooperative side-chain rotational transitions and quarter-stagger displacements on a microsecond time scale, (ii) structures previously deemed stable on a hundred nanosecond time scale are unstable over the microsecond time scale, and (iii) conversely, structures previously deemed unstable did not account for the correct side-chain packing and once the correct symmetry is considered the structures become stable for over a microsecond, due to tightly interdigitated side chains, which lock into highly regular polar zippers with inter-side-chain and backbone-side-chain hydrogen bonds. With these insights, we built Q40 monomeric models with different combinations of arc and hairpin turns and tested them for stability. The stable monomers were further probed as a function of repeat length. Our results are consistent with the aggregation threshold. These results explain and reconcile previously reported experimental and model discrepancies about polyglutamine aggregate structures.
authors.affiliation: Department of Physics, North Carolina State University, Raleigh, North Carolina 27695-8202, United States.
authors.forename: Viet Hoang
authors.initials: VH
authors.lastname: Man
authors.affiliation: Department of Physics, North Carolina State University, Raleigh, North Carolina 27695-8202, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Roland
authors.affiliation: Department of Physics, North Carolina State University, Raleigh, North Carolina 27695-8202, United States.
authors.forename: Celeste
authors.initials: C
authors.lastname: Sagui
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D006860:Hydrogen Bonding; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D055550:Protein Stability; D013997:Time Factors
chemical_list: D000682:Amyloid; D010455:Peptides; C097188:polyglutamine
keywords: Aggregation; amyloid fibrils; antiparallel sheets; parallel sheets; polyglutamine diseases; steric zippers