Scientists at the Chalmers University of Technology in Sweden say they have disproved the prevailing theory of how DNA binds itself. It is not, they claim, as is generally believed, hydrogen bonds which bind together the two sides of the DNA structure. Instead, water is the key. The paper describing their discovery (“Hydrophobic catalysis and a potential biological role of DNA unstacking induced by environment effects”), which could open doors for a new understanding in medical research and life sciences, appears in PNAS.

“Hydrophobic base stacking is a major contributor to DNA double-helix stability. We report the discovery of specific unstacking effects in certain semihydrophobic environments. Water-miscible ethylene glycol ethers are found to modify structure, dynamics, and reactivity of DNA by mechanisms possibly related to a biologically relevant hydrophobic catalysis. Spectroscopic data and optical tweezers experiments show that base-stacking energies are reduced while base-pair hydrogen bonds are strengthened. We propose that a modulated chemical potential of water can promote `longitudinal breathing’ and the formation of unstacked holes while base unpairing is suppressed,” the investigators wrote.

“Flow linear dichroism in 20% diglyme indicates a 20–30% decrease in persistence length of DNA, supported by increased flexibility in single-molecule nanochannel experiments in polyethylene glycol. A limited (3–6%) hyperchromicity but unaffected circular dichroism is consistent with transient unstacking events while maintaining an overall average B-DNA conformation. Further information about unstacking dynamics is obtained from the binding kinetics of large thread-intercalating ruthenium complexes, indicating that the hydrophobic effect provides a 10 to 100 times increased DNA unstacking frequency and an “open hole” population on the order of 10−2 compared to 10−4 in normal aqueous solution.

“Spontaneous DNA strand exchange catalyzed by polyethylene glycol makes us propose that hydrophobic residues in the L2 loop of recombination enzymes RecA and Rad51 may assist gene recombination via modulation of water activity near the DNA helix by hydrophobic interactions, in the manner described here. We speculate that such hydrophobic interactions may have catalytic roles also in other biological contexts, such as in polymerases.

The research team said it has shown that the secret to DNA’s helical structure may be that the molecules have a hydrophobic interior, in an environment consisting mainly of water. The environment is therefore hydrophilic, while the DNA molecules’ nitrogen bases are hydrophobic, pushing away the surrounding water. When hydrophobic units are in a hydrophilic environment, they group together, to minimize their exposure to the water.

The role of the hydrogen bonds, which were previously seen as crucial to holding DNA helixes together, appears to be more to do with sorting the base pairs, so that they link together in the correct sequence.

The discovery is crucial for understanding DNA’s relationship with its environment, noted Bobo Feng, PhD, one of the researchers behind the study and a postdoc at Chalmers University of Technology.

“Cells want to protect their DNA, and not expose it to hydrophobic environments, which can sometimes contain harmful molecules,” said Feng. “But at the same time, the cells’ DNA needs to open up in order to be used. We believe that the cell keeps its DNA in a water solution most of the time, but as soon as a cell wants to do something with its DNA, like read, copy, or repair it, it exposes the DNA to a hydrophobic environment.”

Reproduction, for example, involves the base pairs dissolving from one another and opening up. Enzymes then copy both sides of the helix to create new DNA. When it comes to repairing damaged DNA, the damaged areas are subjected to a hydrophobic environment, to be replaced. A catalytic protein creates the hydrophobic environment. This type of protein is central to all DNA repairs, meaning it could be the key to fighting many serious sicknesses.

Understanding these proteins could yield many new insights into how we could, for example, fight resistant bacteria, or potentially even cure cancer, according to the scientists. Bacteria use a protein called RecA to repair their DNA, and the researchers believe their results could provide new insight into how this process works, potentially offering methods for stopping it and thereby killing the bacteria.

In human cells, the protein Rad51 repairs DNA and fixes mutated DNA sequences, which otherwise could lead to cancer.

“To understand cancer, we need to understand how DNA repairs. To understand that, we first need to understand DNA itself,” continued Feng. “So far, we have not, because we believed that hydrogen bonds were what held it together. Now, we have shown that instead it is the hydrophobic forces which lie behind it. We have also shown that DNA behaves totally differently in a hydrophobic environment. This could help us to understand DNA, and how it repairs. 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.”