Molecular insights into the inhibition of early stages of Aβ peptide aggregation and destabilization of Alzheimer's Aβ protofibril by dipeptide D-Trp-Aib: A molecular modelling approach.

Amyloid beta (Aβ) peptide aggregates rapidly into the soluble oligomers, protofibrils and fibrils to form senile plaques, a neurotoxic component and pathological hallmark of Alzheimer's disease (AD). Experimentally, it has been demonstrated the inhibition of an early stages of Aβ aggregation by a dipeptide D-Trp-Aib inhibitor, but its molecular mechanism is still unclear. Hence, in the present study, we used molecular docking and molecular dynamics (MD) simulations to explore the molecular mechanism of inhibition of an early oligomerization and destabilization of preformed Aβ protofibril by D-Trp-Aib. Molecular docking study showed that the D-Trp-Aib binds at the aromatic (Phe19, Phe20) region of Aβ monomer, Aβ fibril and hydrophobic core of Aβ protofibril. MD simulations revealed the binding of D-Trp-Aib at the aggregation prone region (Lys16-Glu22) resulted in the stabilization of Aβ monomer by π-π stacking interactions between Tyr10 and indol ring of D-Trp-Aib, which decreases the β-sheet content and increases the α-helices. The interaction between Lys28 of Aβ monomer to D-Trp-Aib could be responsible to block the initial nucleation and may impede the fibril growth and elongation. The loss of hydrophobic contacts between two β-sheets of Aβ protofibril upon binding of D-Trp-Aib at the hydrophobic cavity resulted in the partial opening of β-sheets. This also disrupts a salt bridge (Asp23-Lys28) leading to the destabilization of Aβ protofibril. Binding energy calculations revealed that van der Waals and electrostatic interactions maximally favours the binding of D-Trp-Aib to Aβ monomer and Aβ protofibril respectively. The residues Tyr10, Phe19, Phe20, Ala21, Glu22, Lys28 of Aβ monomer, whereas Leu17, Val18, Phe19, Val40, Ala42 of protofibril contributing for the interactions with D-Trp-Aib. Thus, the present study provides structural insights into the inhibition of an early oligomerization of Aβ peptides and destabilization of Aβ protofibril, which could be useful to design novel inhibitors for the treatment of AD.