RESUMO
ß-wrapins are engineered binding proteins of which different mutants can bind and sequester amyloidogenic proteins amyloid-ß (Aß), islet amyloid polypeptide (IAPP), and α-synuclein (α-syn), thereby inhibiting their aggregation into amyloid fibrils. ß-wrapin AS10 is capable of binding and sequestering all three amyloidogenic monomers with micro-molar affinity, with its N-terminal domains remaining flexible and non-functional. Here, we computationally investigated the hypothesis that the anti-amyloid properties of AS10 can be amplified by redesigning its currently non-functional N-terminal domain with particular combinations of canonical and non-canonical amino acids (ncAAs) that can mimic the binding and inhibitory anti-amyloid function of curcumin, using a combination of molecular docking and molecular dynamics simulations. Our simulations suggest that the inhibitory mechanism attributed to the binding of the computationally designed AS10 N-terminal domain to the Aß fibril can act simultaneously to its sequestering properties for Aß which are attributed to the core of AS10. Thus, our study proposes that the N-terminal domain of AS10 can be further modified to amplify its anti-amyloid properties, resulting in a ß-wrapin that may simultaneously prohibit elongation to existing amyloid fibrils and also sequester amyloid monomers.
