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DNA folding subscribes to the chaos theory (Video)

11/08/2010
Suzanne E. Winter

Researchers use molecular dynamics to visualize the various folding processes of a small DNA hairpin.

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Researchers from the Joint Institute for Research in Biomedicine (IRB)-Barcelona Supercomputing Centre (BSC) have recorded the folding process of a small DNA hairpin in real time. The team was able to visualize the time-dependent structural and dynamic details of the process using a molecular dynamics (MD) approach.

Nucleic acid folding provides information about DNA and RNA function and activity in a cell; the structure of single strand DNA (ssDNA) hairpin can have a large impact on its binding activity during translation and can influence the secondary structure of the resulting RNA. But researchers have struggled to characterize these processes, leading to disagreement on a comprehensive mechanisms of nucleic acid folding.

Portella used molecular dynamics to visualize the folding of small DNA hairpin. Source: IRB Barcelona and Guillem Portella.

To visualize the nucleic acid folding process, Guillem Portella, a member of the Molecular Modeling and Bioinformatics Group at IRB Barcelona, and Modesto Orozco, a professor of biochemistry and molecular biology at the University of Barcelona, performed twenty MD simulations for the short oligo d(GCGAAGC). MD is a technique that predicts the movement of molecules—based on physical principles such as force, mass, and acceleration—to create an animated simulation of these movements. “You follow the positions of each of the molecules you are considering as they move over time to create a trajectory that captures a tiny window of motion in close to native conditions,” said Portella. To simulate just one nanosecond of motion that follows a ssDNA from an unfolded confirmation to a hairpin conformation, Portella and Orozco made over one million MD calculations.

The twenty trials were analyzed against the known low energy and hairpin conformations of the oligo to examine the folding trajectories. The researchers found a high level of variation in the MD data, suggesting that nucleic acid folding mechanisms vary significantly for each molecule and cannot be reduced to a limited number of transition states. Further, when the group raised the temperature to decrease folding time, they noticed secondary effects of nonnative folding that may imitate the native conformation, producing similar but non-functional molecules.

Reductionist descriptions of folding mechanisms attempt to simplify nucleic acid, but MD and other real-time imaging techniques have shown an enormous amount of variation in nucleic acid folding. Portella believes that scientists are becoming more comfortable with the unique folding patterns of different nucleic acid molecules. “The community tends to appreciate these more chaotic models much more than before,” he says. “It’s similar to what people are seeing in protein folding—there’s not a unique way of going from one structure to another.”

The paper, “Multiple routes to characterize the folding of a small DNA hairpin,” was published 15 Sept. 2010 at Angewandte Chemie: International Edition.