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New research funded by the Leverhulme Trust reveals a subtle physical force that helps identical DNA sequences to pair up.

Scientists at ³Ô¹ÏºÚÁÏ, in collaboration with Cambridge, Oxford, Sorbonne, and Harvard University researchers, have uncovered compelling evidence that double-stranded DNA molecules can physically recognise matching DNA sequences without the help of proteins, shedding new light on one of biology's most fundamental, yet mysterious, processes – a first stage of genetic recombination.

The findings, ,  shows clear evidence that double stranded DNA molecules carrying identical genetic information tend to spend more time close together than unrelated DNA sequences.

This phenomenon is suggested to proceed through a subtle, sequence-dependent physical interaction. 

While these findings are not the first evidence of this effect (other studies include those by l, G. S. Baldwin et al, and ) this study evaluated the strength of the effect – the value of the recognition energy, as well as the role and effect of counterions in solution on dsDNA-dsDNA (double-stranded DNA) pairing.

This discovery could help explain the earliest stages of homologous recombination – a critical biological process that allows cells to repair damaged DNA, maintain genetic stability, and promote the genetic development beyond mutations.

How does DNA find its matching partner?

Every day, the DNA inside our cells experiences damage. To repair this damage accurately, cells often rely on homologous recombination, a process in which a damaged DNA locates another, undamaged, DNA molecule carrying the overall same genetic sequence and uses it as a template for repair. Recombination also occurs during the formation of sperm and egg cells, when DNA from the mother and father is mixed and reshuffled to create the genetic blueprint passed on to children. 

Although the interaction per base pair is extremely weak, it becomes significant when long DNA molecules are involved and could help explain how homologous DNA segments find each in the haystack of the cell interior." Alexei Kornyshev Chair of Chemical Physics at ³Ô¹ÏºÚÁÏ

For this process to work correctly, matching genes – carrying instructions for the same biological functions – must recognize and exchange with one another accurately, like “eye for an eye” or “kidney for kidney.” Mistakes in this exchange can cause serious genetic disorders, cell damage, or processes linked to aging.

While scientists understand many of the molecular steps involved in recombination, a longstanding question has remained unresolved: how do two matching DNA molecules recognise each other in the first place?

Traditional explanations have focused on proteins, the cell’s factory workers, that actively bring homologous (almost identical) genes together. However, for decades some researchers have proposed a more intriguing possibility that DNA itself might possess an inherent ability to recognise matching sequences through purely physical interactions, even in the absence of proteins. Until now, experimental evidence for such a mechanism has been limited.

A highly sensitive DNA nanosensor

To investigate the problem, the team developed a minimal DNA-based nanosensor capable of measuring extremely weak interactions between pairs of double-stranded DNA molecules with unprecedented precision. Using this system, the researchers compared interactions between DNA duplexes that shared the same sequence and those that did not.

They found that matching, also known as homologous, DNA sequences consistently exhibited stronger attraction than non-matching sequences in the presence of physiologically relevant concentrations of divalent ions such as magnesium.

Physical recognition through electrostatics

To explain the observations, the team developed a quantitative theoretical framework based on electrostatic interactions, based on the theory the first version of which was . Its underlying principle was that although the genetic letters of DNA are buried inside the double helix, their sequence influences the distribution of electrical charge along the molecule's surface. When two DNA molecules share the same sequence, these charge patterns become correlated, creating what the researchers describe as "electrostatic helical coherence".
This coherence generates a weak but measurable attraction between homologous DNA duplexes.

The results suggest that DNA sequence information is not completely hidden within the double helix. Instead, matching sequences may leave a subtle physical signature that allows double-stranded DNA molecules to recognise one another directly, without unzipping.

Potential biological relevance

The researchers caution that homologous recombination in living cells remains a highly complex process involving numerous proteins and molecular machines.

However, the measured physical attraction could help matching DNA molecules find one another in the crowded environment of the cell nucleus, potentially making subsequent protein-mediated steps more efficient and minimising recombination errors.

The work done here paves the way forward for future endeavours in attempt of understanding how DNA molecules can recognize one another and self-organize prior genetic recombination in a complex cell environment." Ehud Haimov Research Associate in Theoretical Chemical Physics, ³Ô¹ÏºÚÁÏ

The nanosensor used in the study was designed to mimic some of the physical constraints found in densely packed biological environments, where DNA molecules are often confined and concentrated.

The findings therefore support the hypothesis that purely physical, sequence-nonspecific interactions between intact double-stranded DNA, universally different between homologous and heterologous sequences, contribute to homologous recognition and may play a role in the earliest stages of DNA repair and recombination.

Alexei Kornyshev, Chair of Chemical Physics at ³Ô¹ÏºÚÁÏ, said: “For many years scientists have debated whether double-stranded DNA molecules can recognise matching sequences directly, without proteins. In that may underpin this effect, which has been later developed in series of publications. 

“Measurements identifying the effect, without unravelling its nature, have been reported first by electrophoretic measurements of Takashi Oyama and co-workers, and a paper of our ³Ô¹ÏºÚÁÏ team that has reported observation of homology segregation in liquid-crystals of DNA. This was followed by Harvard compelling single molecule magnetic bead experiments . 

“Now, the 2026 measurements provided one more quantitative evidence that such recognition exists, but it also allowed to estimate the recognition free energy. Although the interaction per base pair is extremely weak, it becomes significant when long DNA molecules are involved and could help explain how homologous DNA segments find each in the haystack of the cell interior."

Andy Stannard, Research Associate in Experimental Biophysics and DNA Nanotechnology at ³Ô¹ÏºÚÁÏ’s Department of Chemistry, said of the research: “Since interactions between DNA duplexes are relatively weak, we developed an experimental platform to probe these interactions. 

“The solution was to tether homologous (identical) or heterologous (different) duplexes together, via a third, short duplex. Incorporating fluorescent moieties in the synthetic DNA strands that composed these nanosensors meant that the homologous recognition – greater interactions between homologous duplexes – led to an enhanced fluorescence signature that could be easily detected.”

Lorenzo di Michele, from Cambridge University, said: “The success of this experimental approach is a demonstration of the power of DNA nanotechnology, a technique introduced that uses synthetic DNA molecules to construct nanoscale structure and devices with precisely controlled shape and functions. Here, we used DNA nanotechnology to accurately measure DNA itself in a very non-invasive way, which was necessary given how subtle the homology interactions are.”

Mara Prentiss, from Harvard University, said: “The interaction that recognizes homology and helps homologous genes to pair is found to be weak, but it must not be strong! We want homologous genes to temporary pair, for the proteins to subsequently do the recombination job, but not irreversibly stick to each other, which would have been a deadly situation.” 

³Ô¹ÏºÚÁÏ team member, Research Associate in Theoretical Chemical Physics, Ehud Haimov, said: “We were all amazed how well the theory captured experimental results. The work done here paves the way forward for future endeavours in attempt of understanding how DNA molecules can recognize one another and self-organize prior genetic recombination in a complex cell environment, shedding light on one of the fundamental processes underlying heredity and evolution.”