According to clinical studies, the development of Alzheimer's disease (AD) is linked to the abnormal aggregation of amyloid-β (Aβ) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils. The most acceptable therapeutic strategy for the treatment of AD is to block the Aβ aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH₂ (rk10), which acts as a potent inhibitor of Aβ aggregation and efficiently disaggregates pre-assembled Aβ fibrils. However, the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils remains obscure. To investigate the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils, molecular dynamics (MD) simulations have been performed in the present study. The molecular docking analysis using AutoDock Vina predicted favourable binding of rk10 with the N-terminal and central hydrophobic core (CHC) residues of Aβ₄₂ monomer (-5.3 kcal mol^-1), and with the residues of chain A of Aβ₄₂ protofibril structure (-6.9 kcal mol^-1). The MD simulations depicted higher structural stability of Aβ₄₂ monomer in the presence of rk10. Notably, rk10 prevented the sampling of β-sheet rich structures of Aβ₄₂ monomer by reducing the side-chain contacts between N-terminal and C-terminal residues of Aβ₄₂ monomer. The per-residue binding free energy analysis highlighted the significant contribution of Phe19 and Glu22 of Aβ₄₂ monomer in binding with rk10, which corroborate with the ¹H NMR (nuclear magnetic resonance) spectra of Aβ₄₂ monomer + rk10 complex that depicted a change in the chemical shifts of amide protons of Phe19 and Glu22. Further, rk10 destabilized the Aβ₄₂ protofibril structure by lowering the number of interchain hydrogen bonds. The binding free energy analysis predicted lower binding affinity between Aβ₄₂ protofibril chains in the presence of rk10 as compared to Aβ₄₂ protofibril alone. The insights into the inhibitory mechanism of rk10 against Aβ aggregation and disassembly of fibrils will be beneficial for the design and development of potent anti-amyloid inhibitors.

	Year	Citations

About