Binding Modes of a Glycopeptidomimetic Molecule on Aβ Protofibrils: Implication for Its Inhibition Mechanism

We recently reported that a glycopeptidomimetic molecule significantly delays the fibrillization process of Aβ₄₂ peptide involved in Alzheimer's disease. However, the binding mode of this compound, named 3β, was not determined at the atomic scale, hindering our understanding of its mechanism of action and impeding structure-based design of new inhibitors. In the present study, we performed molecular docking calculations and molecular dynamics simulations to investigate the most probable structures of 3β complexed with Aβ protofibrils. Our results show that 3β preferentially binds to an area of the protofibril surface that coincides with the protofibril dimerization interface observed in the solid-state NMR structure 5KK3 from the PDB. Based on these observations, we propose a model of the inhibition mechanism of Aβ fibrillization by compound 3β.