SEVI Inhibits Aβ Amyloid Aggregation by Capping the β-Sheet Elongation Edges

Inhibiting the aggregation of amyloid peptides with endogenous peptides has broad interest due to their intrinsically high biocompatibility and low immunogenicity. Here, we investigated the inhibition mechanism of the prostatic acidic phosphatase fragment SEVI (semen-derived enhancer of viral infection) against Aβ42 fibrillization using atomistic discrete molecular dynamics simulations. Our result revealed that SEVI was intrinsically disordered with dynamic formation of residual helices. With a high positive net charge, the self-aggregation tendency of SEVI was weak. Aβ42 had a strong aggregation propensity by readily self-assembling into β-sheet-rich aggregates. SEVI preferred to interact with Aβ42, rather than SEVI themselves. In the hetero-aggregates, Aβ42 mainly adopted β-sheets buried inside and capped by SEVI in the outer layer. SEVI could bind to various Aβ aggregation species – including monomers, dimers, and proto-fibrils – by capping the exposed β-sheet elongation edges. The aggregation processes Aβ42 from the formation of oligomers to conformational nucleation into fibrils and fibril growth could be inhibited as their β-sheet elongation edges being occupied by the highly charged SEVI. Overall, our computational study uncovered the molecular mechanism of experimentally observed inhibition of SEVI against Aβ42 aggregation, providing novel insights into the development of therapeutic strategies against Alzheimer's disease.