Multi-site Cleavage of Amyloid-β by a Minimal 5-mer Catalytic Peptide: Mimicking Serine Protease Activity via Hydrophobic Anchoring

The development of small synthetic catalytic peptides, or catalytides, offers a promising therapeutic strategy for the targeted degradation of amyloid-beta (Abeta). Among these, the pentapeptide SKGQA mimics the proteolytic activity of serine proteases despite its minimal size. However, the molecular mechanism enabling such a short, highly flexible peptide to execute cleavage across multiple sites remains unclear. In this study, we combined HADDOCK docking and extended molecular dynamics (MD) simulations to investigate the dynamic interaction between SKGQA and the central hydrophobic cluster (CHC, residues 17-21) of Abeta. Our MD simulations reveal a cooperative mechanism underlying this activity. The hydrophobic C-terminal Ala5 residue anchors SKGQA within the Abeta CHC region, stabilizing the bound complex while potentially interfering with Abeta self-assembly through steric hindrance. Simultaneously, while the C-terminus remains anchored, the hydrophilic N-terminal Ser1 residue is positioned in spatial proximity to multiple adjacent backbone carbonyl carbons, including Glu22 and Asp23. Within this anchored conformational ensemble, thermal fluctuations allow Ser1 to stochastically attack these neighboring carbonyl targets. This combination of site-specific hydrophobic anchoring and probabilistic catalytic targeting provides a clear structural rationale for the peptide's multi-site cleavage capability.