Study shows how two matching DNA strands hybridize to generate double-stranded DNA

Nanoscientists and theoretical physicists from UNSW Medicine & Health’s EMBL Australia Node in Single Molecule Science collaborated to decipher the intricate mechanics of determining how quickly two matched strands of DNA may completely come together—or hybridize—to generate double-stranded DNA. Their results were reported in Nucleic Acids Research.

A theory offered around 50 years ago stated that the first contact that leads to continued bonding of the string of matching bases on the DNA strands—termed nucleating interactions—determines how rapidly DNA strands hybridize. Due to the complexity of DNA biology, this notion has never been confirmed until recently.

There are an enormous number of pathways through which two fully dissociated strands can bind to each other. DNA stands don’t come together into a fully hybridized duplex in an instant. At some point, only two or three base pairs will spontaneously join. This is what a nucleating event is.”

Lawrence Lee, Associate Professor, EMBL Australia Node for Single Molecule Science, School of Medical Sciences, University of New South Wales

We built a simple mathematic model, which only has two parameters, and asked: if we only knew how many nucleating interactions there were, and how stable they were, can we predict hybridization rates? And we found that the answer was yes,” A/Prof. Lee added.

To put this idea to the test quantitatively, the researchers converted the original theory into a mathematical formula that they could compare to their synthetic DNA experiments.

According to A/Prof Lee, the predictive ability of their model was dependent on its simplicity.

If a mathematical model contains too many different parameters, it is no longer useful for making predictions. The key difference to previous attempts to understand DNA hybridization rates was that our model had few parameters and was tested against DNA sequences that should not form secondary structures.”

Lawrence Lee, Associate Professor, EMBL Australia Node for Single Molecule Science, School of Medical Sciences, University of New South Wales

When DNA strands fold over themselves, secondary structures emerge, which might possibly conceal nucleation and binding sites.

The theory is, if this initial small interaction is stable enough, it will go from there to a very fast zippering up of the DNA strands. If the limiting step is nucleating, then it follows that if you have more nucleating states, then the DNA should hybridize faster.”

Lawrence Lee, Associate Professor, EMBL Australia Node for Single Molecule Science, School of Medical Sciences, University of New South Wales

This research has the potential to help us better comprehend biological processes. The capacity to forecast or regulate the pace of DNA hybridization might potentially aid in the refinement or expansion of nanotechnologies’ applicability.

With this new insight, researchers can regulate the pace of DNA binding by adjusting the quantity and stability of nucleation contacts. This may be accomplished in a variety of methods, including changing the reaction temperature, DNA sequence, and solution ionic strength.

We can generate high resolution images using DNA paint—fluorescent strands of DNA used as tags for microscopy—because we are measuring the binding and unbinding of DNA to individual molecules. But, it can take a long time to acquire data. If we could rationally design sequences for DNA paint, so that it can bind more rapidly, then we could reduce the acquisition time for super-resolution imaging,” concluded A/Prof Lee.

Source:
Journal reference:

Hertel, S., et al. (2022) The stability and number of nucleating interactions determine DNA hybridization rates in the absence of secondary structure. Nucleic Acids Research. doi.org/10.1093/nar/gkac590.

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