Simulations open window on microscopic world

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"We find the features that the polymer should have so it optimally binds the DNA and effectively delivers the DNA to the target.” – Arthi Jayaraman
"We find the features that the polymer should have so it optimally binds the DNA and effectively delivers the DNA to the target.” – Arthi Jayaraman

Unlike most chemical and biological engineers, Arthi Jayaraman never gets her hands wet…at least, not in her lab. But as a highly successful teacher and researcher in CU-Boulder’s chemical and biological engineering department, she’s as passionate about chemistry and engineering as if she spent all her time handling test tubes.

Instead, she and her students create computer simulations of molecular behavior that are based on computational chemistry and thermodynamics. The results enhance information obtained experimentally by other researchers, sometimes providing crucial information needed to optimally engineer a new drug or material.

Bio-compatible polymers that could be used one day as carrier molecules to deliver gene therapy are one application where Jayaraman’s team has shown that the way the polymer’s molecules are structured can have a large impact.

Running a short movie on her desktop computer that is almost as colorful as it is informative, she easily demonstrates through simulation how the polymer’s branched structure, as it binds and wraps around a therapeutic gene (a segment of DNA), affects its ability to deliver the treatment efficiently to its targeted cells.

“If the polymer binds the DNA too tightly, then it won’t let go of it upon reaching the target site in the cell,” Jayaraman says, clenching her fist enthusiastically to demonstrate. “If the polymer binds the DNA too loosely, then the DNA is not protected from the harmful proteins in the cell. We find the features that the polymer should have so it optimally binds the DNA and effectively delivers the DNA to the target.”

Using computer simulation to show how these polymers function dynamically at the molecular level, she is able to guide her synthetic chemist collaborator, Todd Emrick at the University of Massachusetts Amherst, on the structure and architectural features he should keep in his polymers to have the desired outcome in in-vitro and in-vivo gene delivery experiments.

Each simulation focuses on a small window in a larger system, so as to capture all the molecular details of an event that occurs on the timescale of just a few hundred nanoseconds. Based on sophisticated mathematical algorithms, these molecular simulations show the time evolution of all the molecules in that small window.

The calculations for each simulation can take as much as one or two days or even a week to run on large supercomputers, but the result is a high-impact movie stretching the real timeframe of nanoseconds into a few seconds of visualization.

Jayaraman, who received the Outstanding Undergraduate Teaching Award in her department last year and was recently named the Patten Faculty Fellow, is working on four different types of simulation projects funded by the National Science Foundation and Department of Energy. Simulations open window on microscopic world Departments – Chemical and Biological Engineering

In addition to simulating how polymers bind to DNA, she and a few of her graduate students are working to improve the design of solar cells containing organic polymer-based materials. Funded by a prestigious Early Career Award from the Department of Energy, she is zooming into the nanometer length scale to show how the organization of the polymers at the molecular level could be impacting the macroscopic power efficiency of the device.

“There can be huge changes in efficiency with the optimal organization of these polymers,” says Jayaraman, who is funded to work on the project for the next five years. She also works closely with the experimentalists at the National Renewable Energy Laboratory to connect her nanoscale understanding to the macroscale properties.

In a third project, funded by NSF with Associate Professor Wounjhang Park of electrical, computer, and energy engineering, she is using her computer simulations to study assembly of functionalized nanoparticles for metamaterial design.

Possibly the most exciting project, although not yet funded she says, is aimed at improving the efficacy of platinum-based cancer drugs by shedding light on how proteins process them in our body.

“These cancer drugs bind themselves to DNA in a way that allows the proteins in our body to recognize and process them to stop the growth of bad cancerous cells,” she explains. “How well the repair proteins in our body bind to these drug-DNA sites is directly connected to how well the drug performs. Molecular simulations in our group show that specifically one of these repair proteins, HMGB1a, more easily binds to the drug-DNA site when it has to spend less energy while bending the drug-DNA molecule.”

Chemical engineering students can look forward to a new graduate-level course on molecular simulation, which Jayaraman will offer next year.

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