Supramolecular Recognition of a DNA Four‐Way Junction by an M ₂ L ₄ Metallo‐Cage, Inspired by a Simulation‐Guided Design Approach

DNA four-way junctions (4WJs) play an important biological role in DNA repair and recombination, and viral regulation, and are attractive therapeutic targets. Compounds that recognise the junction structure are rare; in this work, we describe cationic metallo-supramolecular M₂L₄ cages as a new type of 4WJ binder with nanomolar affinities. A combination of molecular dynamics (MD) simulations and biophysical experiments show that the size and shape of a compound comprising square planar Pd or Pt and anthracene-based ligands is an excellent fit for the 4WJ cavity. Whilst the cage is also capable of binding to three-way junctions (3WJs) and Y-fork structures, we show that the 4WJ is the preferred DNA target, and that duplex B-DNA is not a competitor. Among 3WJs, T-shape bulged 3WJs are bound more preferably than perfect Y-shaped 3WJs. Whilst previous work studying M₂L₄ metallo-supramolecular cages has focused on binding inside their structures, this work exploits the external aromatic surfaces of the supramolecule, creating a supramolecular guest that ideally matches the DNA host cavity. This approach allows available structures to be identified as potential junction binders and then screened for their fit to a nucleic acid junction target using simulations. This has potential to significantly accelerate discovery.