Ionic interactions involving DNA phosphates are ubiquitous and essential across all kingdoms of life. For the first time, their catalytic potential has been demonstrated in a variety of asymmetric transformations through ion-pairing interactions in water. Credit: National University of Singapore
Scientists at NUS have found that DNA’s phosphate groups can guide chemical reactions like molecular “hands.”
Chemists at the National University of Singapore (NUS) have discovered an unexpected way to use deoxyribonucleic acid (DNA). Beyond its role as the carrier of genetic information, DNA can also serve as a powerful tool to make the production of medicinal compounds more efficient. The team found that specific parts of DNA, known as phosphates, can act like tiny “hands” that help guide chemical reactions, ensuring that the process produces the desired mirror-image form of a molecule.
Many medicines are chiral, which means their molecules exist in two mirror-image forms—similar to how right and left hands reflect each other. These two versions can have dramatically different effects in the body. Often, only one version of a drug is beneficial, while the other may be ineffective or even harmful. Producing just the correct form is a major challenge in pharmaceutical chemistry. The NUS team’s DNA-based method offers a simpler and more environmentally friendly way to achieve this selectivity.
In nature, DNA and proteins naturally attract one another because of their opposite charges. DNA’s phosphate groups carry negative charges, while many of the building blocks that make up proteins are positively charged. The researchers, led by Assistant Professor Zhu Ru-Yi from the NUS Department of Chemistry, investigated whether this natural electrostatic attraction could be harnessed to steer chemical reactions toward specific outcomes and generate the desired products.
Pinpointing DNA’s Active Sites
They discovered that certain phosphate groups in DNA can attract and guide positively charged reactants during a chemical reaction. This is similar to a magnet gently pulling a metal bead into the correct orientation. This “ion-pairing” effect holds the reactants close and in a particular orientation, steering the reaction in a specific way to produce only one mirror-image product. The team demonstrated this effect across several different types of chemical reactions.
To understand exactly which parts of DNA were responsible, the researchers developed a new experimental method called “PS scanning”. The researchers systematically replaced individual phosphates along DNA with closely related look‑alikes, then repeated the reactions.
If changing a particular position caused the selectivity to drop, it indicated that the original phosphate at that site was important for guiding the reaction. Computer simulations were carried out in collaboration with Professor Zhang Xinglong from The Chinese University of Hong Kong to validate these findings.
Toward Greener and Smarter Chemical Manufacturing
The research was published in the scientific journal Nature Catalysis.
Asst Prof Zhu said, “Nature never uses DNA phosphates as catalysts, but we have shown that if designed properly, they can act like artificial enzymes.”
“Beyond being a conceptual breakthrough, this method could make chemical manufacturing more sustainable and environmentally friendly, especially for producing complex, high-value molecules used in pharmaceutical products,” added Asst Prof Zhu.
Looking ahead, the team plans to explore more ways to use DNA phosphates to create chiral (mirror-image) compounds for drug development.
Reference: “DNA phosphates are effective catalysts for asymmetric ion-pairing catalysis in water” by Zhaoyang Li, Yang Zheng, Qi Zhao, Yihan Li, Adon Yap, Xinglong Zhang and Ru-Yi Zhu, 31 October 2025, Nature Catalysis.
DOI: 10.1038/s41929-025-01437-z
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