New experiment finds evidence of an overlooked force that keeps DNA stable

There could be another force, even stronger than a hydrogen bond, holding our DNA together, new research suggests.

First discovered back in the 1950s, the double helix structure of our genetic material has since become iconic, although we’re still figuring out how all its pieces fit together.

Appearing like a twisted ladder, the rungs are nitrogen base-pairs, held together by some of the strongest intermolecular attractions there are: hydrogen bonds.

Connecting both sides of the ladder, these ultra-strong links are often described as the major stabilising force in DNA. But perhaps there’s another, more important factor at play.

DNA replication usually occurs through the help of several enzymes, which ‘unzip‘ DNA molecules by breaking their hydrogen bonds. It turns out, however, that’s not the only way to destabilise the double helix.

By testing the DNA in an environment more hydrophobic than normal, researchers at Chalmers University of Technology in Sweden have now shown for the first time that this water-repelling force is enough to unravel the double helix all on its own.

“The main stabiliser of the DNA double helix is not the base-pair hydrogen bonds but coin-pile stacking of base pairs,” the authors conclude, “whose hydrophobic cohesion, requiring abundant water, indirectly makes the DNA interior dry so that hydrogen bonds can exert full recognition power.”

In other words, because DNA base pairs are naturally water-repelling, in a normal water solution, they stack together to stay safe from their surroundings – kind of like a colony of huddling penguins.

It’s unclear if enzymes in nature do something similar, but given other similar models, the team thinks this is a distinct possibility.

Breaking these groupings apart requires the opposite effect. By gradually adding a hydrophobic solution of polyethylene glycol – which is often used in cars as antifreeze – the team has shown that DNA loses its structure, and that this happens right as its surroundings go from water-loving to water-repelling.

“Cells want to protect their DNA, and not expose it to hydrophobic environments, which can sometimes contain harmful molecules,” explains chemical engineer and lead author Bobo Feng.

“But at the same time, the cells’ DNA needs to open up in order to be used.”

As such, Feng and his colleagues propose that a normal cell keeps its DNA in a water solution until it wants to read, copy or repair its DNA. Only then does the cell create a more hydrophobic environment, through the use of enzymes with a similar function to polyethylene glycol.

hydrofob(Yen Strandqvist/Chalmers University of Technology)

Steven Brenner, a molecular biophysicist at NASA, told ScienceAlert this was an important discovery that demonstrates a new way enzymes might ‘melt’ the double helices of DNA for transcription or repair. Still, he warns, the way in which many mainstream media outlets have been covering this paper is not entirely accurate.

Despite what many are reporting, he says the results do not suggest hydrogen bonds are unimportant for DNA formation. Only that hydrophobic forces also play a crucial role.

And this is hardly a new concept. Models that include hydrophobic interactions in the double helix date back at least to the 1990s, and today, there are whole labs devoted to this avenue of research.

Way back in 1997, scientists began to question the notion that hydrogen bonds alone can keep the two strands of a DNA double helix together. That textbook explanation, it seemed, was inadequate, and several years later, in 2004, a study found hydrogen bonding was not required for the stability of base pairs.

Just a few years ago, in 2017, a study showed that a lack of complementary hydrogen bonds doesn’t really bother cells, and that synthetic bases are successfully transcribed and translated anyway, using only hydrophobic forces.

Together, these results suggest that perhaps the forces we’ve observed in nature aren’t the only ones responsible for the double helix.

“It would be very easy to say complementary hydrogen bonds are what define DNA and RNA,” said biochemist Floyd Romesberg, an author of the 2017 paper.

“But we’ve found that forces other than hydrogen bonding can productively participate in every step of information storage and retrieval.”

Yet as much as we’ve learned over the years, there are still limits to the conclusions we can draw from these models.

“One of the sad lessons of physical organic chemistry from the last century,” Benner told ScienceAlert, “is that efforts to separately model the behaviour of molecules as the consequence of different factors .. tells you more about the chemist doing the modelling than it tells you about the molecules themselves.”

These frameworks, for instance, can either be evaluated on their ability to merely explain DNA or on their ability to actually make it. Personally, Benner believes the latter analysis is more objective, because explanations on their own can often just convince us we understand what’s going on.

“If, however, our models actually allow us to make things, then they must really have some reality behind them,” he argues.

In the end, Benner says both hydrogen bonding and hydrophobicity have proved necessary to make natural DNA, and this double-pronged model is currently used both in human medicine and in NASA’s search for alien life.

The new research adds to this idea by providing a possible biological mechanism for this process.

“Nobody has previously placed DNA in a hydrophobic environment like this and studied how it behaves, so it’s not surprising that nobody has discovered this until now,” says Feng.

The findings were published in PNAS.

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