title: Modeling amyloid-beta as homogeneous dodecamers and in complex with cellular prion protein.
abstract: Soluble amyloid beta (Aβ) peptide has been linked to the pathology of Alzheimer's disease. A variety of soluble oligomers have been observed to be toxic, ranging from dimers to protofibrils. No tertiary structure has been identified as a single biologically relevant form, though many models are comprised of highly ordered β-sheets. Evidence exists for much less ordered toxic oligomers. The mechanism of toxicity remains highly debated and probably involves multiple pathways. Interaction of Aβ oligomers with the N-terminus of the cellular form of the prion protein (PrP(c)) has recently been proposed. The intrinsically disordered nature of this protein and the highly polymorphic nature of Aβ oligomers make structural resolution of the complex exceptionally challenging. In this study, molecular dynamics simulations are performed for dodecameric assemblies of Aβ comprised of monomers having a single, short antiparallel β-hairpin at the C-terminus. The resulting models, devoid of any intermolecular hydrogen bonds, are shown to correlate well with experimental data and are found to be quite stable within the hydrophobic core, whereas the α-helical N-termini transform to a random coil state. This indicates that highly ordered assemblies are not required for stability and less ordered oligomers are a viable component in the population of soluble oligomers. In addition, a tentative model is proposed for the association of Aβ dimers with a double deletion mutant of the intrinsically disordered N-terminus of PrP(c). This may be useful as a conceptual working model for the binding of higher order oligomers and in the design of further experiments.
authors.affiliation: Wallingford, Connecticut, United States of America. sgallion@comcast.net
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gallion
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions