Serotonin and Melatonin Show Different Modes of Action on Aβ₄₂ Protofibril Destabilization

Alzheimer's disease (AD) is associated with the aberrant self-assembly of amyloid-β (Aβ) protein into fibrillar deposits. The disaggregation of Aβ fibril is believed as one of the major therapeutic strategies for treating AD. Previous experimental studies reported that serotonin (Ser), one of the indoleamine neurotransmitters, and its derivative melatonin (Mel) are able to disassemble preformed Aβ fibrils. However, the fibril-disruption mechanisms are unclear. As the first step to understand the underlying mechanism, we investigated the interactions of Ser and Mel molecules with the LS-shaped Aβ₄₂ protofibril by performing a total of nine individual 500 ns all-atom molecular dynamics (MD) simulations. The simulations demonstrate that both Ser and Mel molecules disrupt the local β-sheet structure, destroy the salt bridges between K28 side chain and A42 COO^-, and consequently destabilize the global structure of Aβ₄₂ protofibril. The Mel molecule exhibits a greater binding capacity than the Ser molecule. Intriguingly, we find that Ser and Mel molecules destabilize Aβ₄₂ protofibril through different modes of action. Ser preferentially binds with the aromatic residues in the N-terminal region through π-π stacking interactions, while Mel binds not only with the N-terminal aromatic residues but also with the C-terminal hydrophobic residues via π-π and hydrophobic interactions. This work reveals the disruptive mechanisms of Aβ₄₂ protofibril by Ser and Mel molecules and provides useful information for designing drug candidates against AD.