title: Insights into structure, stability, and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations.
abstract: Nine genetically inherited neurodegenerative diseases are linked to abnormal expansions of a polyglutamine (polyQ) encoding region. Over the years, several structural models for polyQ regions have been proposed and confuted. The cross-beta-spine steric zipper motif, identified recently for the GNNQQNY peptide, represents an attractive model for amyloid fibers formed by polyQ fragments. Here we report a detailed molecular dynamics investigation of polyQ models assembled by cross-beta-spine steric zipper motifs. Our simulations indicate clearly that these assemblies are very stable. Glutamine side chains contribute strongly to the overall stability of the models by fitting perfectly within the zipper. In contrast to GNNQQNY zipper motifs, hydrogen bonding interactions provide a significant contribution to the overall stability of polyQ models. Molecular dynamics simulations carried out on monomeric polyQ forms (composed by 40-60 residues) show clearly that they can also assume structures stabilized by steric zipper motifs. Based on these findings, we build monomeric polyQ models that can explain recent data on the toxicity exerted by these species. In a more general context, our data suggests that polyQ models with interdigitated side chains can provide a structural rationale to several literature experiments on polyQ formation, stability, and toxicity.
authors.affiliation: Istituto di Biostrutture e Bioimmagini, CNR, I-80134 Naples, Italy. luciana.esposito@unina.it
authors.forename: Luciana
authors.initials: L
authors.lastname: Esposito
authors.forename: Antonella
authors.initials: A
authors.lastname: Paladino
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: Luigi
authors.initials: L
authors.lastname: Vitagliano
mesh_terms: D003198:Computer Simulation; D046911:Macromolecular Substances / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry* / Q000633:toxicity
chemical_list: D046911:Macromolecular Substances; D010455:Peptides; C097188:polyglutamine