Binding of Inositol Stereoisomers To Model Amyloidogenic Peptides

作者：Li Grace; Rauscher Sarah; Baud Stephanie; Pomes Regis^*

来源：Journal of Physical Chemistry B, 2012, 116(3): 1111-1119.

DOI：10.1021/jp208567n

The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer%26apos;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 beta-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 beta-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.

• 出版日期2012-1-26