Supercomputing DNA Packing in Nuclei at TACC

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Aaron Dubrow writes that researchers at the University of Texas Medical Branch are exploring DNA folding and cellular packing with supercomputing power from TACC.

A biological mystery lies at the center of each of our cells, namely: how one meter of DNA can be wadded up into the space of a micron (or one millionth of a meter) within each nucleus of our body. The nuclei of human cells are not even the most crowded biological place that we know of. Some bactiophages — viruses that infect and replicate within a bacterium — have even more concentrated DNA.

“How does it get in there?” B. Montgomery (Monte) Pettitt, a biochemist and professor at the University of Texas Medical Branch, asks. “It’s a charged polymer. How does it overcome the repulsion at its liquid crystalline density? How much order and disorder is allowed, and how does this play a role in nucleic acids?”

Using the Stampede and Lonestar5 supercomputers at The University of Texas at Austin’s Texas Advanced Computing Center (TACC), Pettitt investigates how phages’ DNA folds into hyper-confined spaces.

Writing in the June 2017 issue of the Journal of Computational Chemistry, he explained how DNA may overcome both electrostatic repulsion and its natural stiffness.

Sharp Twists are the Key

The introduction of sharp twists or curves into configurations of DNA packaged within a spherical envelope significantly reduces the overall energies and pressures of the molecule, according to Pettitt.

He and his collaborators used a model that deforms and kinks the DNA every 24 base pairs, which is close to the average length that is predicted from the phage’s DNA sequence. The introduction of such persistent defects not only reduces the total bending energy of confined DNA, but also reduces the electrostatic component of the energy and pressure.

“We show that a broad ensemble of polymer configurations is consistent with the structural data,” he and collaborator Christopher Myers, also of University of Texas Medical Branch, wrote.

Insights like these cannot be gained strictly in the lab. They require supercomputers that serve as molecular microscopes, charting the movement of atoms and atomic bonds at length- and time-scales that are not feasible to study with physical experiments alone.

In the field of molecular biology, there’s a wonderful interplay between theory, experiment and simulation,” Pettitt said. “We take parameters of experiments and see if they agree with the simulations and theories. This becomes the scientific method for how we now advance our hypotheses.”

Problems like the ones Pettitt is interested in cannot be solved on a desktop computer or a typical campus cluster, but require hundreds of computer processors working in parallel to mimic the minute movements and physical forces of molecules in a cell.

Pettitt is able to access TACC’s supercomputers in part because of a unique program known as the University of Texas Research Cyberinfrastructure (UTRC) initiative, which makes TACC’s computing resources, expertise and training available to researchers within the University of Texas Systems’ 14 institutions.

Computational research, like that of Dr. Pettitt, which seeks to bridge our understanding of physical, chemical, and ultimately biological phenomena, involves so many calculations that it’s only really approachable on large supercomputers like TACC’s Stampede or Lonestar5 systems,” said Brian Beck, a life sciences researcher at TACC.

“Having TACC supercomputing resources available is critical to this style of research,” Pettitt said.

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