👤 Michael J. Hannon

Nucleic acid junctions are key to many biological functions from recombination and repair to viral nucleic acid insertion and are an attractive, functional biomolecular target. We describe a quadruple-stranded diplatinum helicate that binds both three-way (3WJ) and four-way DNA junctions (4WJ). This allows us to probe the relative importance of size and shape in junction-binder design. Despite the helicate's tetragonal symmetry/shape being compatible with the 4WJ, microscale thermophoresis (MST), isothermal calorimetry (ITC), and gel electrophoresis competition experiments demonstrate that this metallo-supramolecule displays a stronger affinity for 3WJs (K_d = 12 nM) than for 4WJs (K_d > 4 μM) and other DNA structures. The experimental findings are supported by molecular dynamics simulations that reveal the critical role of size. While the open form of the 4WJ is promoted when the helicate is in the cavity, the helicate's small size means it is unable to maintain π contacts with all four junction base-pairs simultaneously. Although the helicate is slightly too large for the smaller 3WJ cavity, simulations and experiments show that it can open up the cavity (increasing the junction's hydrodynamic radius) by disrupting a base pair. The flexible helicate also responds to the cavity upon binding by favoring one enantiomer and allowing the helicate to adopt a stable final structure inside the 3WJ that is an induced fit of the two dynamic structures (supramolecule and DNA). This contrasts with previous lock-and-key examples of junction recognition and opens up new possibilities for how to design DNA and RNA junction-binding compounds. Show less

DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its genetic message, and, implicitly, its functions. Currently, there are several mechanisms known to be involved in DNA binding. These mechanisms are covalent and non-covalent interactions. The covalent interaction or metal base coordination is an irreversible binding and it is represented by an intra-/interstrand cross-link. The non-covalent interaction is generally a reversible binding and it is represented by intercalation between DNA base pairs, insertion, major and/or minor groove binding, and electrostatic interactions with the sugar phosphate DNA backbone. In the present review, we focus on the types of DNA–metal complex interactions (including some representative examples) and on presenting the methods currently used to study them. Show less