Using cutting-edge cryo-electron microscopy, scientists at the University of Leicester have captured the first detailed “molecular movie” showing DNA being unzipped at the atomic level. The movie reveals how cells start copying their genetic material.
Hexameric helicases are molecular machines powered by nucleotides that unwind DNA to start replication in all life forms. However, key details about how they work—like where and how DNA strands separate, how unwinding continues, and how nucleotide use connects to DNA movement—are still not fully understood.
In this study, scientists used cryo-electron microscopy (cryo-EM) to visualize a helicase enzyme (nature’s DNA unzipping machine) unwinding DNA.
The team captured detailed snapshots showing how this molecular motor unzips the DNA double helix, much like a tiny zipper. Although scientists have long understood that cells must unzip DNA to replicate it, this is the first time they’ve observed the mechanism in such precise detail.
Dr Taha Shahid, from the University of Leicester’s Institute of Structural and Chemical Biology and lead author on the paper, said: “Now we can watch the entire process unfold, in a moment-by-moment fashion, revealing the precise mechanics of one of life’s most fundamental processes.”
Previously, it was believed that helicase works by brute force. This new study operates through an elegant mechanism that uses cellular fuel (ATP) as a precise trigger.
Hexameric helicases function like a six-piston molecular engine. Each “piston” activates sequentially, propelling the helicase along the DNA. Instead of forcibly separating the DNA strands, they release built-up tension like a compressed spring. This natural release of tension allows the DNA to unwind smoothly.
The “entropy switch” mechanism represents an entirely new understanding of molecular motors’ operation. Additionally, researchers resolved a long-standing puzzle about how cells replicate DNA in both directions. They discovered that two helicase machines collaborate at specific DNA sites to create “replication forks,” enabling efficient simultaneous copying of both DNA strands.
Dr Shahid said: “The helicase mechanism we’ve uncovered appears to be evolutionarily conserved from viruses to humans, providing a universal blueprint for understanding DNA replication across all domains of life. From a medical perspective, many viruses – including poxviruses, papillomaviruses (which can cause certain cancers), and polyomaviruses – rely on similar helicase machinery to replicate. Our detailed structural insights could guide the development of precisely targeted antiviral therapies that disrupt viral replication without harming human cells.”
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Dr Alfredo De Biasio, senior author on the paper from KAUST and the University of Leicester, added: “This work represents a significant advance in our understanding of the molecular machinery of life. By combining structural biology with sophisticated computational methods, we’ve revealed what this molecular machine looks like and how it actually works.”
“Nature has evolved an incredibly efficient nanoscale machine in the helicase – understanding how it works could inspire the design of synthetic molecular devices that use similar principles for technological applications.”
Professor John Schwabe, Director of Leicester’s Institute for Structural and Chemical Biology, who established the cryo-electron microscopy facility at the University of Leicester, added: “This is another example of how our world-leading facility is contributing to revealing the critical fundamental mechanisms that underpin life.”
Journal Reference
- Shahid, T., Danazumi, A.U., Tehseen, M. et al. Structural dynamics of DNA unwinding by a replicative helicase. Nature (2025). DOI: 10.1038/s41586-025-08766-w
