Scientists at the University of Leicester have captured the first detailed "molecular movie" showing DNA being unzipped at the atomic level – revealing how cells begin the crucial process of copying their genetic material.
The groundbreaking discovery, published in the prestigious journal Nature , could have far-reaching implications, helping us to understand how certain viruses and cancers replicate.
Using cutting edge cryo-electron microscopy, the team of scientists were able to visualise a helicase enzyme (nature's DNA unzipping machine) in the process of unwinding DNA. DNA helicases are essential during DNA replication because they separate double-stranded DNA into single strands, allowing each strand to be copied.
Dr Taha Shahid, from the University of Leicester's Institute of Structural and Chemical Biology and lead author on the paper, said: "We recorded multiple snapshots showing how this molecular motor methodically separates the DNA double helix. It's like a molecular-scale zipper in action and while scientists have long known that cells need to unzip their DNA to copy it, we have never before been able to see exactly how this happens.
"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."
The researchers found that rather than working by brute force as previously assumed, the helicase operates through an elegant mechanism that uses cellular fuel (ATP) as a precise trigger.
It functions like a six-piston molecular engine - each piston "fires" in sequence, driving the machine forward along the DNA. Crucially, instead of pushing the strands apart directly, it releases built-up tension - like letting go of a compressed spring - allowing the DNA to unwind naturally.
Dr Shahid said: "This "entropy switch" mechanism is fundamentally different from how we thought molecular motors worked. We also solved a long-standing mystery about how cells coordinate DNA copying in both directions, discovering that two helicase machines work together at specific DNA sites, establishing "replication forks" that allow efficient copying of both strands simultaneously."
The research was an international collaboration between the University of Leicester and the King Abdullah University of Science and Technology (KAUST) in Saudi Arabia, which provided core funding and The Midlands Regional Cryo-EM Facility at the Leicester Institute of Structural and Chemical Biology (LISCB), which provided essential infrastructure for the work.
Dr Shahid continued: "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 development of precisely targeted antiviral therapies that disrupt viral replication without harming human cells."
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 been able to reveal not just what this molecular machine looks like, but 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."
