On the Molecular Mechanism of Beta-Amyloid Aggregation Inhibition by KLVFF

The accumulation of beta-amyloid (Aβ) oligomers is a critical hallmark for different neurodegenerative conditions, including Alzheimer's disease. The short peptide KLVFF, derived from the central hydrophobic domain of Aβ, binds to Aβ oligomers and interferes with Aβ aggregation. However, the underlying molecular mechanism of action of this peptide remains to be elucidated. This work addresses this question by studying the interaction between Aβ11-42 (Aβ peptide with 32 amino acids length, from residue 11 to 42) hexamer models and an increasing number (n =1, 3, 6) of randomly positioned KLVFF peptides using triplicate microsecond-scale molecular dynamics (MD) simulations. Our findings revealed that KLVFF interacts non-specifically with the fibril model, maintaining a disordered secondary structure. This interaction induces conformational changes at the ends of the hexamer, leading to the gradual detachment of terminal monomers from the fibril. Structural and energetic data suggest an inhibitory mechanism based on the loss of structural integrity and the prevention of ordered Aβ addition at the fibril ends. This proposal differs from the mechanism previously postulated in the literature, according to which KLVFF would disrupt Aβ aggregation by binding to the central hydrophobic domain at an Aβ region that matches the peptide sequence in an amyloid-like secondary conformation. The validity of our computational findings was corroborated by circular dichroism experiments, which confirmed the ability of the KLVFF peptide to reduce the formation of β-sheet secondary structures in Aβ solutions, with a concentration- and incubation time-dependent effect. Additionally, thioflavin T aggregation assays supported the role of KLVFF in reducing the Aβ aggregation propensity with no evidence of KLVFF self-aggregation. These results provide key insights for the rational design of novel Aβ aggregation inhibitors mimicking KLVFF as fibril end destabilizers and hinders of oligomer elongation