ATP Converts Aβ₄₂ Oligomer into Off-Pathway Species by Making Contact with Its Backbone Atoms Using Hydrophobic Adenosine

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.