The impact of water on the ambivalent behavior and paradoxical phenomenon of the amyloid-β fibril protein

Abstract

Abstract:The crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water's thermodynamic and kinetic solvation effects. As regards the water's character, its hindered-rotation barriers are also considered. The following protein molecules considered here are: the Aβ 40 (PDB ID: 2LMN), Aβ 42 (PDB ID: 5KK3 and 2NAO) and the double-layered Aβ 17−42 fibril. We discuss: (i) extracellular Aβ 40 and Aβ 42 fibril monomers exhibit an ambivalent propensity to transform into a helical form toward the N-term region and a β-strand-like form near the C-terminal; (ii) interfacial water molecules play a crucial role in protein-protein interactions, as molecular dynamics simulations have shown a significant impact on the protein-protein binding; (iii) it is shown that the spontaneous dimerization process of the Aβ 42 fibril protein in water occurs via a two-step nucleation-accommodation mechanism; (iv) MD simulations of the double-layered Aβ 17−42 fibril model show that the C ↔ C interface appears more energetically favorable than the N ↔ N interface due to large hydrophobic contacts; (v) the water's role in the HET-s prion and in the Aβ fibrillar aggregates; (vi) it was found that the monomer-oligomer equilibrium spontaneously dissociates into stable monomeric species when they are incubated up to 3 μm for a longer time (>1 week) in a physiological buffer.