Adenosine triphosphate (ATP) is newly expected to be involved in the clearance of amyloid β 1-42 (Aβ42) fibril and its precursors, Aβ42 oligomer. Meanwhile, the microscopic mechanism of the role in dissolving the protein aggregate still remains elusive. Aiming to elucidate the mechanism, we examined effects of ATP on the conformational change and thermodynamic stability of the protomer dimer of Aβ42 pentamer and tetramer, Aβ42(9), by employing all-atom molecular dynamics simulations. We observed interprotomer twisting and intraprotomer peeling of Aβ42(9). These conformational changes remarkably accelerate dissociation of the protomer dimer. However, the presence of ATP itself has no positive effect on dissociation processes of the protomer dimer and a monomer from the dimer, indicating its irrelevance to decomposition of the Aβ42 oligomer. Rather, it could be supposed that ATP prevents additional binding and rebinding of Aβ42 monomers to the Aβ42 oligomer and it then converts Aβ42 oligomer into an off-pathway species which is excluded from Aβ42 fibril growth processes. Interestingly, hydrophobic adenosine in ATP makes contact with Aβ42(9) on its backbone atoms, with respect to both Aβ42 monomers on the edge of Aβ42(9) and dissociated Aβ42 monomers in Aβ42(9). These roles of ATP would be applied without regard to the structural polymorphism of the Aβ42 fibril.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry