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

The development of small synthetic catalytic peptides, or “catalytides,” offers a promising therapeutic strategy for the targeted degradation of amyloid-beta (A β ). Among these, the pentapeptide SKGQA mimics the proteolytic activity of serine proteases despite its minimal size. However, the molecular mechanism enabling such a short peptide to achieve effective cleavage at multiple sites remains unclear. In this study, we utilized HADDOCK docking and molecular dynamics (MD) simulations to investigate the interaction between SKGQA and the A β (17–42) region. Our results demonstrate that SKGQA operates through a highly dynamic process, where the substrate serves as a scaffold to stabilize “serine protease-like” active geometries from a flexible conformational ensemble. We identified distinct “stable binding” and “stochastic attack” modes, explaining the peptide’s ability to facilitate both high-probability and multi-site cleavage. Given its minimal size, SKGQA may also benefit from enhanced accessibility to dense amyloid environments compared to larger proteases. These findings provide a fundamental understanding of minimal enzymatic function and offer a transformative platform for designing next-generation, cost-effective catalytides.