Exploring the Impact of C-Terminal Based Pentapeptides on the Disassembly of Aβ₄₂ Fibrils

An effective therapeutic strategy to suppress Alzheimer's disease (AD) progression is to disrupt β-sheet rich neurotoxic soluble amyloid-β (Aβ) aggregates. Previously, we identified new pentapeptides (RVVPI and RIAPA) with notably enhanced ability to block Aβ₄₂ aggregation as compared to Aβ₄₂ C-terminal derived peptide RIIGL using integrated computational protocol. In this work, the potential of RIIGL, RVVPI, and RIAPA for the structural destabilization of Aβ₄₂ protofibril was assessed by molecular dynamics (MD) simulations and in vitro studies. The binding free energy analysis depicts that charged residues influence Aβ₄₂ protofibril-pentapeptide interactions. Notably, RVVPI displays a more pronounced destabilization effect than other peptides due to higher conformational fluctuations, and disruption of salt bridge (K28-A42) interactions in Aβ₄₂ protofibril. RVVPI exhibited highest inhibitory activity (Inhibition=66.2 %, IC₅₀=5.57±0.83 μM) against Aβ₄₂ aggregation consistent with computational results. Remarkably, RVVPI displayed ~4.5 fold lower IC₅₀ value as compared to RIIGL. ThT and TEM studies highlighted the enhanced efficiency of RVVPI (62.4 %) in the disassembly of pre-formed Aβ₄₂ fibrils than RIIGL and RIAPA. The combined in silico and in vitro studies identified a new peptide, RVVPI, as an efficient inhibitor of Aβ₄₂ fibrillation and disassembly of Aβ₄₂ aggregates.