title: Binding of inositol stereoisomers to model amyloidogenic peptides.
abstract: The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer's disease. scyllo-Inositol is a stereochemistry-dependent in vitro inhibitor of amyloid formation. As the first step to elucidate its mechanism of action, we present molecular dynamics simulations of scyllo-inositol and its inactive stereoisomer, chiro-inositol, with simple peptide models, alanine dipeptide (ADP) and (Gly-Ala)(4). We characterize molecular interactions and compute equilibrium binding constants between inositol and ADP as well as, successively, monomers, amorphous aggregates, and fibril-like β-sheet aggregates of (Gly-Ala)(4). Inositol interacts weakly with all peptide systems considered, with millimolar to molar affinities, and displaces the conformational equilibria of ADP but not of the (Gly-Ala)(4) systems. However, scyllo- and chiro-inositol adopt different binding modes on the surface of β-sheet aggregates. These results suggest that inositol does not inhibit amyloid formation by breaking up preformed aggregates but rather by binding to the surface of prefibrillar aggregates.
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: Sarah
authors.initials: S
authors.lastname: Rauscher
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baud
authors.forename: Régis
authors.initials: R
authors.lastname: Pomès
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013237:Stereoisomerism
chemical_list: D000682:Amyloid; D010455:Peptides; D007294:Inositol