Water Dynamics And Interactions Inside Amyloid-Beta Fibrils

Aggregation of Aβ-peptides is important in the etiology of Alzheimer's Disease (AD). Studies have documented the presence of mobile water molecules in Aβ-fibrils, even in relatively anhydrous areas. One main proposed mechanism of Aβ toxicity is the disruption of water and/or ion fluxes at neuronal cell membranes. We compared multiple long all-atom explicit solvent molecular dynamics simulations starting from two structural models of Aβ (1-40 residues) fibrils having 3-fold rotational symmetry (PDB-ID's: 2LMP, 2M4J). The 2M4J structure is based on an AD brain-seeded fibril whereas 2LMP is synthetic. 2M4J rapidly develops gaps at the sides of the fibril, allowing bidirectional diffusion of water and ions from the bulk phase in and out the central longitudinal core of the fibril. We observed similar but less marked changes in 2LMP. We suggest a link between the presence of D23-K28 salt bridges and gap openings, as this salt bridge is mostly absent in 2LMP. The K28 residues partially block the 2LMP gaps, as they are not linked to the D23 residues via salt bridges, preventing the water flow to the core of the fibril. The diffusion of water molecules beginning in the core is biphasic and can be separated into two regimes: confined motion and diffusion in the presence of obstacles. The waters in the 2M4J core are more mobile than those of 2LMP, as the core of 2LMP is more confined. Waters reside in the 2M4J core for an average of 767±135 picoseconds, and in the 2LMP core for 1581±374 picoseconds. Of these core waters, those closer to the protein are less mobile than those further away as measured by Debye-Waller factor. These observations suggest that Aβ-fibrils may act as aqueous pores that might disrupt water and ion fluxes if inserted into a cell membrane.