title: Binding mechanism of inositol stereoisomers to monomers and aggregates of Aβ(16-22).
abstract: Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Aβ42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Aβ fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Aβ(16-22), an amyloid-forming peptide fragment of full-length Aβ, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to β-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Aβ protofibrils and disrupts their lateral stacking into amyloid fibrils.
authors.affiliation: Department of Biochemistry, University of Toronto, 27 King's College Circle, Toronto, Ontario, Canada M5S 1A1.
authors.forename: Grace
authors.initials: G
authors.lastname: Li
authors.forename: Régis
authors.initials: R
authors.lastname: Pomès
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D007294:Inositol / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22); D007294:Inositol