Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-beta (A beta) peptides into beta-sheet-rich oligomers and insoluble amyloid fibrils. Experimental studies reported that 1,2-(dimethoxymethano)fullerene (DMF), a water-soluble fullerene derivative, inhibits strongly A beta peptide aggregation at the early stage. However, the interaction and binding mechanisms are not well understood. In this study, we have investigated the detailed interaction of a DMF molecule with a fibrillar hexamer of full-length A beta(42) and the resulting structural alterations by performing multiple all-atom explicit solvent molecular dynamics (MD) simulations. Starting from different initial states with a minimum distance of 2 nm between the DMF and the A beta protofibril, our MD simulations show that the DMF binds to the A beta protofibril via both slow and fast binding processes. Three dominant binding sites are identified: the central hydrophobic core (CHC) site (17LVFFA21), the turn site (27NKGAI31), and the C-terminal beta-sheet site consisting of the smallest side-chain residue glycine and hydrophobic residues (31IIGLMVGGVVI41). Binding energy analyses reveal the importance of pi-stacking interactions, especially in the CHC site, hydrophobic interactions, and curvature matching. Strikingly, we find that the binding of DMF to the turn region can disrupt the D23-K28 salt-bridge that is important for the A beta fibrillation. These results provide molecular insight into the binding mechanism of fullerene to A beta protofibrils and offer new routes for the therapeutic drug design using fullerene derivatives against AD.