Metal-Mediated Base Pairing in Nucleic Acids

Metal-mediated base pairing is an emerging paradigm in which metal ions replace or complement natural hydrogen bonds between nucleobases in DNA and RNA duplexes. By coordinating transition metals such as silver, mercury, copper or gold between suitably modified or mismatched nucleotides, researchers have created stable “metallo-DNA” architectures that retain the canonical helical geometry while introducing novel electronic, optical and catalytic functions. Early work on thymine–HgII–thymine and cytosine–AgI–cytosine pairs demonstrated that metal coordination can mimic, and in some cases surpass, the thermal and structural stability of Watson–Crick pairs. Subsequent advances have extended the concept to include ligand-bearing nucleobases, bifacial uracil derivatives and orthogonal metal ions that confer allosteric control over DNAzyme activity. Metal-mediated base pairs serve as programmable sites for constructing nanoscale wires, sensors and dynamic nanostructures, with potential applications in biosensing, synthetic biology and molecular electronics. Integration of semiconducting polymers into DNA scaffolds has yielded one-dimensional conductive chains, while metal-responsive assembly and disassembly enable stimuli-responsive materials. Global efforts have focused on unravelling fundamental coordination geometries, elucidating the thermodynamics of metal insertion and harnessing enzymatic methods to incorporate these pairs into longer oligonucleotides. The confluence of structural biology, materials science and biochemistry underpins the multidisciplinary growth of metallo-DNA research, promising new avenues for both fundamental insight and technological innovation.

Research from Nature Portfolio

Researchers have engineered a coordination polymer from a thioguanosine analogue that self-assembles with AuI ions into luminescent one-dimensional helical chains structurally akin to natural DNA. Oxidative doping transforms these gold-thiolate fibres into wire-like conductors, demonstrating a route to integrate semiconducting domains site-specifically within DNA materials. In parallel, work on silver-mediated cytosine mismatch duplexes has established that C–AgI–C base pairs form continuous ion chains along duplexes up to 50 nucleotides, yielding robust nanowires with predictable thermodynamics and biostability. These constructs can be enzymatically ligated into longer scaffolds and have been formatted as functional gene parts for cell-free production, marking a key milestone towards scalable, self-assembling nanoelectronic architectures.

Metal-Mediated Base Pairing in Nucleic Acids publication trend

The graph below shows the total number of articles in metal-mediated base pairing in nucleic acids across all publications each year (not limited to Nature Index journals).

Technical terms

Metal-mediated base pair: A noncanonical nucleobase pair in which one or more metal ions bridge two bases via coordinate bonds, replacing hydrogen bonds.

Coordinate bond: A type of covalent bond in which both electrons in the bond originate from the same atom, typically coordinating a metal ion.

Watson–Crick base pair: The canonical hydrogen-bonded pairings between adenine–thymine (or adenine–uracil) and cytosine–guanine in nucleic acids.

DNAzyme: A catalytic DNA molecule that can perform site-specific cleavage or ligation reactions, often modulated by metal cofactors.

Aptamer: A short nucleic acid sequence selected in vitro for high-affinity binding to specific targets, including metal ions.

Oligonucleotide ligation: An enzymatic process that joins short nucleic acid fragments end-to-end to form longer strands.

Allosteric regulation: Modulation of a molecule’s activity or structure through binding of an effector at a site distinct from the active centre.

References

1. Crystal structures and identification of novel Cd2+-specific DNA aptamer. Nucleic Acids Research (2023).
2. Ligase-mediated synthesis of Cu II -responsive allosteric DNAzyme with bifacial 5-carboxyuracil nucleobases. Chemical Science (2024).
3. Organomercury oligonucleotide–polydopamine nanoparticle assemblies discriminate between target sequences by Hg( ii )-mediated base pairing. RSC Advances (2024).
4. The structure of metallo-DNA with consecutive thymine–HgII–thymine base pairs explains positive entropy for the metallo base pair formation. Nucleic Acids Research (2013).
5. Addressing the properties of “Metallo-DNA” with a Ag( i )-mediated supramolecular duplex. Chemical Science (2019).
6. A coordination polymer for the site-specific integration of semiconducting sequences into DNA-based materials. Nature Communications (2017).
7. Construction and characterization of metal ion-containing DNA nanowires for synthetic biology and nanotechnology. Scientific Reports (2019).