The concept of a static Watson-Crick double helix DNA is wrong says new research.
We all know the image of a DNA strand. It has the shape of a double helix. Now scientists are destroying this image with supercomputers. Researchers have imaged in new detail the three-dimensional structure of supercoiled DNA, revealing that its shape is much more dynamic than the well-known double helix.
Various DNA shapes, including figure-8s, were imaged using a powerful microscopy technique by researchers at the Baylor College of Medicine in the US, and then examined using supercomputer simulations run at the University of Leeds.
The supercomputer simulations also show the dynamic nature of DNA. The DNA constantly wiggles and morphs into different shapes, destroying the notion of the static double helix DNA shape.
Dr Sarah Harris from the School of Physics and Astronomy at the University of Leeds, who led the computer simulation research side of the study, said: “This is because the action of drug molecules relies on them recognizing a specific molecular shape – much like a key fits a particular lock.”
The double helix shape of DNA is the popular way to imagine DNA. But the shape of DNA isn’t always that simple, as pointed out in the new study.
Dr Harris said: “When Watson and Crick described the DNA double helix, they were looking at a tiny part of a real genome, only about one turn of the double helix. This is about 12 DNA ‘base pairs’, which are the building blocks of DNA that form the rungs of the helical ladder.
“Our study looks at DNA on a somewhat grander scale – several hundreds of base pairs – and even this relatively modest increase in size reveals a whole new richness in the behavior of the DNA molecule.”
To understand the structure of DNA when it is crammed into cells, the researchers needed to replicate this coiling of DNA.
To investigate how the winding changed what the circles looked like, the researchers wound and then unwound the tiny DNA circles. These DNA segments are 10 million times shorter in length than the DNA contained within human cells.
The researchers devised a test to make sure that the tiny twisted up DNA circles that they made in the laboratory acted in the same way as the full-length DNA strands within human cells, when it is referred to as ‘biologically active’.
They used an enzyme called ‘human topoisomerase II alpha’ that manipulates the twist of DNA. The test showed that the enzyme relieved the winding stress from all of the supercoiled circles, even the most coiled ones, which is its normal job in the human body. This result means that the DNA in the circles must look and act like the much longer DNA that the enzyme encounters in human cells.
“Some of the circles had sharp bends, some were figure-8s, and others looked like handcuffs or racquets or even sewing needles. Some looked like rods because they were so coiled,” said Dr Rossitza Irobalieva, the co-lead author on the publication.
It will take a while until people will be able to digest these new DNA findings and think of DNA as a much more complicated shape that moves.
Dr Harris concludes: “We are sure that supercomputers will play an increasingly important role in drug design. We are trying to do a puzzle with millions of pieces, and they all keep changing shape.”