Mark Bathe - Computer model enables design of complex DNA shapes
Engineers computer-design the most complicated 3-D structures ever made from DNA.
Anne Trafton | MIT News Office
December 3, 2014
MIT biological engineers have created a new computer model that allows them to design the most complex three-dimensional DNA shapes ever produced, including rings, bowls, and geometric structures such as icosahedrons that resemble viral particles.
This design program could allow researchers to build DNA scaffolds to anchor arrays of proteins and light-sensitive molecules called chromophores that mimic the photosynthetic proteins found in plant cells, or to create new delivery vehicles for drugs or RNA therapies, says Mark Bathe, an associate professor of biological engineering.
“The general idea is to spatially organize proteins, chromophores, RNAs, and nanoparticles with nanometer-scale precision using DNA. The precise nanometer-scale control that we have over 3-D architecture is what is centrally unique in this approach,” says Bathe, the senior author of a paper describing the new design approach in the Dec. 3 issue of Nature Communications.
The paper’s lead authors are postdoc Keyao Pan and former MIT postdoc Do-Nyun Kim, who is now on the faculty at Seoul National University. Other authors of the paper are MIT graduate student Matthew Adendorff and Professor Hao Yan and graduate student Fei Zhang, both of Arizona State University.
DNA by design
Because DNA is so stable and can easily be programmed by changing its sequence, many scientists see it as a desirable building material for nanoscale structures. Around 2005, scientists began creating tiny two-dimensional structures from DNA using a strategy called DNA origami — the construction of shapes from a DNA “scaffold” strand and smaller “staple” strands that bind to the scaffold. This approach was later translated to three dimensions.
Designing these shapes is tedious and time-consuming, and synthesizing and validating them experimentally is expensive and slow, so researchers including Bathe have developed computer models to aid in the design process. In 2011, Bathe and colleagues came up with a program called CanDo that could generate 3-D DNA structures, but it was restricted to a limited class of shapes that had to be built on a rectangular or hexagonal close-packed lattice of DNA bundles.
In the new paper, Bathe and colleagues report a computer algorithm that can take sequences of DNA scaffold and staple strands and predict the 3-D structure of arbitrary programmed DNA assemblies. With this model, they can create much more complex structures than were previously possible.
The new approach relies on virtually cutting apart sequences of DNA into subcomponents called multi-way junctions, which are the fundamental building blocks of programmed DNA nanostructures. These junctions, which are similar to those that form naturally during DNA replication, consist of two parallel DNA helices in which the strands unwind and “cross over,” binding to a strand of the adjacent DNA helix.
After virtually cutting DNA into these smaller sections, Bathe’s program then reassembles them computationally into larger programmed assemblies, such as rings, discs, and spherical containers, all with nanometer-scale dimensions. By programming the sequences of these DNA components, designers can also easily create arbitrarily complex architectures, including symmetric cages such as tetrahedrons, octahedrons, and dodecahedrons.
“The principal innovation was in recognizing that we can virtually cut these junctions apart only to reassemble them in silico to predict their 3-D structure,” Bathe says. “Predicting their 3-D structure in silico is central to diverse functional applications we’re pursuing, since ultimately it is 3-D structure that gives rise to function, not DNA sequence alone.”