Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22)

Alzheimer's disease (AD) is a severe neuro-degenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of A beta 42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of A beta fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of A beta(16-22), an amyloid-forming peptide fragment of full-length A beta, 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 beta-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 A beta protofibrils and disrupts their lateral stacking into amyloid fibrils.