Researchers at the University of Cambridge, together with international partners, have uncovered a key mechanism that governs how DNA moves through nanoscale pores. This mechanism plays a pivotal role in many cellular processes and is essential for the next generation of DNA‑based sensing devices.
Nanopores are minute apertures that let a single DNA strand pass while generating characteristic electrical currents. Those currents are the basis for reading genetic information at the single‑molecule level. For years, scientists misinterpreted a recurring pattern in the signals, assuming it arose from DNA knots.
Why the Knot Theory Dominated for Decades
The knot idea seemed intuitive: pulling a thread through a tiny hole creates uneven motion whenever the thread tangles. Many researchers extrapolated this picture to DNA, believing that any irregular current spike meant the molecule had formed a knot inside the pore.
Twists, Not Knots, Generate the Observed Patterns
Recent work published in Physical Review X overturns that view. Instead of genuine knots, the DNA frequently adopts coiled structures called plectonemes. These look more like a twisted telephone cord than a knotted rope, and they produce prolonged electrical signatures that differ markedly from the brief blips generated by true knots.
Evidence of an Overlooked Mechanism
The team examined DNA translocation using both glass and silicon‑nitride nanopores across a broad voltage range. They observed “tangled” events—moments when multiple DNA segments occupied the pore simultaneously—far more often than knot statistics would predict. The frequency rose with higher voltage and longer DNA fragments, hinting at an additional driving force.
Electroosmotic Flow Spins the DNA
Investigations revealed that the electric field inside a nanopore sets the surrounding water into motion, a phenomenon known as electroosmotic flow. This flowing water exerts a torque on the helical DNA, propagating twist along the molecule and prompting sections outside the pore to coil into plectonemes.
Because plectonemes can expand and persist throughout the entire passage, their electrical footprint is longer than that of a knot, which tightens and slips through quickly. Computer simulations that modeled realistic forces confirmed that the ability of DNA to transmit twist dictates plectoneme formation.
Disrupting Twist Propagation Validates the Model
To test the hypothesis, the researchers engineered “nicked” DNA strands—molecules with deliberate single‑strand breaks that block twist transmission. These nicked strands produced far fewer plectoneme events, proving that the spread of torque along the backbone is essential.
The result also suggests a novel strategy for detecting DNA damage: breaks that hinder twist could be identified directly from nanopore current signatures.
Implications for Biological Understanding and Technology
Beyond the laboratory, DNA routinely twists and coils as enzymes remodel the genome, meaning that plectonemes are likely integral to cellular DNA organization and stability. Recognizing their impact refines models of how chromosomes behave in vivo.
For diagnostic platforms, the ability to sense or control DNA twisting could dramatically boost sensitivity, enabling the detection of subtle mutational events or early markers of disease‑related DNA damage.