Supramolecular Recognition of a DNA Four‐Way Junction by an M2L4 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.