title: Direct Correlation of Cell Toxicity to Conformational Ensembles of Genetic Aβ Variants.
abstract: We report a systematic analysis of conformational ensembles generated from multiseed molecular dynamics simulations of all 15 known genetic variants of Aβ42. We show that experimentally determined variant toxicities are largely explained by random coil content of the amyloid ensembles (correlation with smaller EC50 values; R(2) = 0.54, p = 0.01), and to some extent the helix character (more helix-character is less toxic, R(2) = 0.32, p = 0.07) and hydrophobic surface (R(2) = 0.37, p = 0.04). Our findings suggest that qualitative structural features of the amyloids, rather than the quantitative levels, are fundamentally related to neurodegeneration. The data provide molecular explanations for the high toxicity of E22 variants and for the protective features of the recently characterized A2T variant. The identified conformational features, for example, the local helix-coil-strand transitions of the C-terminals of the peptides, are of likely interest in the direct targeting of amyloids by rational drug design.
authors.affiliation: DTU Chemistry, Technical University of Denmark , Kemiorvet 206, DK-2800 Kongens Lyngby, Denmark.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Somavarapu
authors.affiliation: DTU Chemistry, Technical University of Denmark , Kemiorvet 206, DK-2800 Kongens Lyngby, Denmark.
authors.forename: Kasper P
authors.initials: KP
authors.lastname: Kepp
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease; Amyloid beta; coil; structural ensembles; toxicity