Computational design of a β-wrapin's N-terminal domain with canonical and non-canonical amino acid modifications mimicking curcumin's proposed inhibitory function.

β-wrapins are engineered binding proteins of which different mutants can bind and sequester amyloidogenic proteins amyloid-β (Aβ), islet amyloid polypeptide (IAPP), and α-synuclein (α-syn), thereby inhibiting their aggregation into amyloid fibrils. β-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.