Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Supercoiled DNA is far more dynamic than the 'Watson-Crick' double helix

13.10.2015

Researchers have imaged in unprecedented 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 image shows the structure of the DNA calculated with the supercomputer simulations (in colour) superimposed upon the cryo-electron tomography data (in white or yellow). (There is no superimposition onto cryo-electron tomography data for the purple figure-8 shape.) You can see that the familiar double helix has been either simply bent into a circle or twisted into a figure-8.

Credit: Thana Sutthibutpong

As reported online today in the journal Nature Communications, the simulations also show the dynamic nature of DNA, which constantly wiggles and morphs into different shapes - a far cry from the commonly held idea of a rigid and static double helix structure.

Improving our understanding of what DNA looks like when it is in the cell will help us to design better medicines, such as new antibiotics or more effective cancer chemotherapies.

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 recognising a specific molecular shape - much like a key fits a particular lock."

The double helix shape has a firm place in the public's collective consciousness. It is referenced in popular culture and often features in art and design. But the shape of DNA isn't always that simple.

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."

There are actually about 3 billion base pairs that make up the complete set of DNA instructions in humans. This is about a metre of DNA. This enormous string of molecular information has to be precisely organised by coiling it up tightly so that it can be squeezed into the nucleus of cells.

To study the structure of DNA when it is crammed into cells, the researchers needed to replicate this coiling of DNA.

Dr Lynn Zechiedrich, the corresponding author for the study from the Baylor College of Medicine, said: "You can't coil linear DNA and study it, so we had to make circles so the ends would trap the different degrees of winding."

To investigate how the winding changed what the circles looked like, the researchers wound and then unwound the tiny DNA circles - 10 million times shorter in length than the DNA contained within our cells - a single turn at a time.

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 our 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.

Dr Rossitza Irobalieva, the co-lead author on the publication, who conducted the work while she was at Baylor, used 'cryo-electron tomography' - a powerful microscopy technique that involves freezing biologically active material - to provide the first three-dimensional images of individual circular DNA molecules. She saw that coiling the tiny DNA circles caused them to form a zoo of beautiful and unexpected shapes.

"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 Irobalieva.

The static images produced by the cryo-electron tomography were then compared to and matched with shapes generated in supercomputer simulations that were run at the University of Leeds. These simulated images provided a higher-resolution view of the DNA and show how its dynamic motion makes its shape constantly change to form a myriad of structures.

The cryo-electron tomography of the tiny DNA circles also revealed another surprise finding.

Base pairs in DNA are like a genetic alphabet, in which the letters on one side of the DNA double helix only pair with a particular letter on the other side. While the researchers expected to see the opening of base pairs - that is, the separation of the paired letters in the genetic alphabet - when the DNA was under-wound, they were surprised to see this opening for the over-wound DNA. This is because over-winding is supposed to make the DNA double helix stronger.

The researchers hypothesise that this disruption of base pairs may cause flexible hinges, allowing the DNA to bend sharply, perhaps helping to explain how a meter of DNA can be jammed into a single human cell.

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."

###

Further information

The research paper, 'The Structural Diversity of Supercoiled DNA', was published online today in Nature Communications.

Dr Sarah Harris received funding from the Biotechnology and Biological Sciences Research Council (BBSRC).

Dr Harris is available for interview. Please contact the University of Leeds press office on 0113 343 4031 or email pressoffice@leeds.ac.uk.

A team of researchers from a number of fields came together to address this fundamental problem. Their YouTube video explains the new results: https://www.youtube.com/watch?v=gwy2lD1reos

Images

Caption: The images show the structure of the DNA calculated with the supercomputer simulations (in colour) superimposed upon the cryo-electron tomography data (in white or yellow). (There is no superimposition onto cryo-electron tomography data for the purple figure-8 shape.) You can see that the familiar double helix has been either simply bent into a circle or twisted into a figure-8.

Download: https://goo.gl/OZWCxa

Credit: Thana Sutthibutpong

Movies

Caption: Supercomputer simulations show how the dynamic motion of the supercoiled DNA causes its shape to change constantly to form a myriad of structures.

Download: https://goo.gl/OvikoV

Credit: Thana Sutthibutpong

Sarah Reed | EurekAlert!

More articles from Life Sciences:

nachricht Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>