DNA’s worm-like moves
DNA may scrunch like a worm to get inside viral shells, a team including Georgia Tech researchers reports in the Journal of Physical Chemistry B. This deeper understanding could lead to new ways to fight pathogens and design powerful DNA transporters.
A critical step in viral replication is the packaging of genetic material. To successfully invade host cells, viral particles must hijack the host’s machinery to make copies of viral genetic material and build protein shells called capsids to house viral DNA or RNA. Scientists have been studying how the genetic material is driven into capsids so they might one day block this step.
Viral capsids are assembled from a number of identical protein subunits, like a soccer ball sewn together from panels. At the lone opening sits a protein complex, called the protein tunnel, through which DNA enters and exits the capsid, analogous to the air valve that allows a soccer ball to be inflated.
The proteins driving this process are among the strongest biological motors known. Most scientists have assumed that these proteins act like levers, grabbing the DNA and applying force along the axis of the DNA to push it into the capsid. In this simple mechanical picture, DNA plays a passive role.
However, all molecules are dynamic, says Harold D. Kim, an associate professor at Georgia Tech’s School of Physics and a coauthor of the study. “They do not stay in one shape, but constantly change their conformation because of thermal fluctuations,” he explains. DNA is not an exception. It is therefore plausible that DNA itself contributes to genome packaging.
A couple of years ago, Stephen C. Harvey, then a professor in the School of Biology at Georgia Tech and now at the University of Pennsylvania, proposed a role for DNA. The role is based on DNA’s ability to interconvert between two alternative structures – called A and B forms – depending on the number of surrounding water molecules. Called the “scrunchworm” hypothesis, it proposes that DNA changes its form when the protein tunnel changes its shape.
According to Kim, proteins composing the tunnel are enzymes that burn ATP to do mechanical work, which alternately widens and shrinks the tunnel itself. The hypothesis suggests that DNA assumes the short A form when the tunnel is narrow and converts to the B form when the tunnel is wide, rather than being pushed directly by the protein tunnel. Thus, the DNA itself produces the actual movement along the tunnel, while proteins only grab and release the DNA at two locations in a coordinated manner to guide it in the right direction.
To test this hypothesis, Harvey, Kim, and James C. Gumbart, an assistant professor in Georgia Tech’s School of Physics embarked on a collaboration. The Kim group had been studying the bending dynamics of DNA that influence genome packaging, and the Gumbart group had expertise in molecular dynamics simulations. James T. Waters, a Ph.D. student in Kim’s group, carried out the molecular dynamics simulations. He and Columbia University research scientist Xiang-Jun Lu performed data analysis. In a previous work, the researchers reported a simple way to visualize the A-B transitions of DNA. The same method was used to characterize the DNA structures inside the protein tunnel.
The researchers simulated interactions between a protein and DNA sequences from a virus. The computer models suggest that the DNA scrunches spontaneously without any lever-like protein motions. If further testing bears out this proposed mechanism, it would demonstrate for the first time that changes in DNA’s shape can produce strong forces.
“These studies also reinforce our rapidly expanding view that DNA is more than just genetic information: It is an active participant in genome packaging and maintenance,” Kim notes.
Although these studies were carried out on a non-pathogenic virus, the resulting insights are most likely broadly applicable, because the same packaging mechanism is used by herpes viruses that cause diseases such as chickenpox, shingles, infectious mononucleosis, and oral and genital lesions.
The authors acknowledge funding from the National Institute of Health and the National Science Foundation.
For more information, contact:
Harold D. Kim
School of Physics
Georgia Institute of Technology
Atlanta, GA 30332
A. Maureen Rouhi