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 Aβ 42 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 Aβ 42 protofibril. The Mel molecule exhibits a greater binding capacity than the Ser molecule. Intriguingly, we find that Ser and Mel molecules destabilize Aβ 42 protofibril through different modes of action. Ser preferentially binds with the aromatic residues in the Nterminal 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 Aβ 42 protofibril by Ser and Mel molecules and provides useful information for designing drug candidates against AD.

Protofibrillar trimer is the critical nucleus for the αS fibril formation, and the tetramer is the minimal stable nucleus. The interactions of DA/NE with αS trimer/tetramer disrupt the backbone H-bonds and destabilize the αS protofibrils.

The accumulation of Tau protein aggregates is a pathological hallmark of tauopathy, including chronic traumatic encephalopathy (CTE). Inhibiting Tau aggregation or disrupting preformed Tau fibrils is considered one of the...

Microsecond all-atom molecular dynamics simulations reveal that melatonin can destabilize the protofilament and filament of tau R3–R4 domains. Its influence on tau structure, binding kinetics and sites, and the disruptive mechanism are studied.

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