DNA binding metal-peptidic helicates as minimal coiled-coil mimics

Abstract

Metal-organic helicates are precisely defined nanoscale assemblies which have been widely used in biological applications due to their high stability, ready synthesis, and selective interactions with DNA. However, most have been formed predominantly from rigid aromatic panels or single, continuous pseudopeptidic chains, limiting their specific interactions with biological systems and potential for variation. Coiled-coils are common structural motifs in DNA binding proteins, enabling precise orientation of DNA binding a-helices. Herein, we merge these two concepts, creating metal-peptidic helicates (c. 3 nm long) which form from three individual, defined, a-helical architectures, with precisely controlled chirality, bridging the typical length scale of metal-organic helicates (1 nm) and coiled coils (c. 10 nm). We synthesise of a series of novel M2L3 metal-peptidic helicates (M = Fe(II) or Ni(II)) using bipyridine functionalised, Aib stabilised, a-helices, in which metal coordination brings together three individual peptide chains in a chiral, supercoiled, structure reminiscent of coiled-coil domains. By changing bipyridine substitution site, the handedness of the helicate structure (ΔΔ or ΛΛ) can be switched independently of peptide sequence. We demonstrate that these helicates possess exceptional stability in water, and are capable of selectively binding DNA three-way junctions (3WJs) over other DNA secondary structures – offering a highly tunable platform for developing selective binders for biological applications.