A DNA origami schematic in the shape of a tetrahedron. Source: Wikipedia user Antony-22. (Licensed via CC BY-SA 3.0)

Researchers might be intrigued by the idea of DNA origami and its potential, but most biologists would rather let engineers or chemists handle the prickly problems of turning the concept of DNA nanostructures into a useful final product.1 Though nearly all labs have access to the necessary experimental materials to make DNA origami, experiment planning and origami design have lagged far behind to the point of inaccessibility. To quote the authors of a computational method for DNA origami development, “in silico design of DNA nanostructures remains a challenge, and all but a few experienced research groups have the expertise to fully implement the methods in practice.”2 Joining in on the growing complexity of DNA origami designs and logic modules will require powerful software, which might be hard to come by.

The urgency of in silico design suites for DNA origami is accelerating thanks to increasingly functional and advanced origami structures. In a presentation given at the March meeting of the American Physical Society, a group of researchers proposed a new and compelling strategy for making DNA origami capsules which self-assemble around their intended cargo for targeted future delivery.3 Far from a one-off prototype, the new research offers an easily deployable schematic for DNA origami capsules which could be calibrated for arbitrary cargo and delivery conditions. This strategy joins similar research using modeling software to design DNA origami in different shapes to develop “smart” drug delivery methods which can bring logic gated disbursal of drug cargo.4 It’s clear that the future of DNA origami is bigger, more complex, and more programmable than the endless proofs of concept in the field thus far, but most research groups aren’t yet equipped with the necessary information technology platform to join in.5 There’s a major discrepancy between what is easily possible in a test tube and what most researchers can design to take advantage of that capability.   

Folding DNA Into A Capsule

Like with all DNA origami, the secret to the new strategy is in the strand hybridization to its complements. Rather than attempting to make many different sticky ends hybridize with each other all in one step in hopes of forming the correct larger structure, the researchers first made cross shaped bendable sections and line shaped scaffolding sections of DNA. The cross shaped sections allowed for the researchers to define the exact geometry of the origami capsule, as the angle of each strand could be easily configured by changing the codons or backbones of the sticky ends. In contrast, the linear scaffold sections simply elongate the reach of each strand from the cross sections and bind to the cargo on one side, allowing for a DNA cage to be built around whatever cargo researchers specify via the linear sections’ codons.

Once the cross shaped sections and linear sections were assembled, putting them in the same geographical location causes them to self assemble by hybridization, trapping the cargo in their interior in the process. While the above will seem like a matter of experimental iteration (known informally as trial and error) until there’s a confirmation of successful self-assembly and cargo capture, the researchers’ use of molecular modeling software saved them a series of headaches when it was time to hit the lab.

The new strategy described in the presentation has the potential to make DNA origami capsules clinically viable, if only researchers could easily tweak the general design to their specific application. Software is understood to be a necessity for making DNA origami with any sort of consistency despite that the first informal description of the concept was realized via manual calculation of binding and molecular forces.6

To make DNA origami structures on the first trial, the researchers needed to:

  • Model the electrostatic forces of the origami’s intended cargo
  • Design several cross shaped sections of DNA with a central anchor which only binds with DNA of a certain sequence such that its 3D structure is angled in the desired direction
  • Design strands of DNA which can only hybridize with the strands that are adjacent to its final intended position within the origami structure
  • Design linear sections of DNA which have exposed external binding domains which are linked to a cargo release mechanism
  • Design linear sections of DNA which have exposed internal binding domains linked to the cargo release mechanism to confirm cargo presence in the origami after self-assembly; if there’s no internal cargo after self assembly, the origami will dissociate and reform again
  • Model the entire completed origami structure in isolation, without cargo
  • Model the completed origami structure with one load of cargo
  • Model the completed origami structure with one load of cargo and also other potential loads of cargo external to the structure
  • Model the completed origami structure both with and without cargo in an environment which contains both intended cargo and irrelevant other molecules which may be inadvertently trapped during self assembly
  • Model the binding of the origami’s release mechanism to its intended target and the subsequent dissociation of the origami’s structure

These aren’t a trivial set of challenges, but addressing the complexity of DNA origami in silico provides for a high level of control over the origami’s features in addition to massively reducing the hands-on time spent in the lab.

What’s The Issue With DNA Origami Design Software?

More recently, software designed specifically for 3D DNA modeling has come about, yet none are dominant in the market or easy enough to use for non-CAD specialists.7 For a process that’s mechanically average in difficulty to execute, DNA origami is cut off from wide use because of the modeling software required for its design.

The dedicated DNA origami software on the market often drops the ball when it comes to simulating interactions between the DNA and anything that isn’t DNA, making it unsuitable for therapeutics development or broader use even if researchers were to purchase it. Researchers have taken the problem of inadequate DNA origami design software into their own hands. Some researchers have resorted to using software packages built for computer graphics rather than for molecular modeling as a result of the extant software’s incompleteness.8 While these innovative solutions are sure to continue, researchers would be better equipped if they had an inclusive and powerful molecular modeling suite which could easily model DNA origami as well as any intended cargo or binding sites.

BIOVIA Biologics is the DNA origami modeling suite that the therapeutic developers of the near future will need to design drug delivery capsules. With Biologics, you’ll be able to bridge the gap between what your team is capable of in the laboratory and what your software is capable of helping you plan. Contact us today to find out how you can use Biologics to start modeling DNA origami capsules and break open the newest frontier of advanced drug delivery systems.

  1.  “Bioengineering: What To Make With DNA Origami.” March 2010, https://www.nature.com/news/2010/100310/full/464158a.html
  2. “Automated Design Of DNA Origami.” 2016, https://aaltodoc.aalto.fi/bitstream/handle/123456789/24661/B1_linko_veikko_2016.pdf?sequence=1
  3. “DNA Origami Wrapped Colloids For Programmable Self-Assembly.” March 2017, http://absimage.aps.org/image/MAR17/MWS_MAR17-2016-009140.pdf
  4. “3D DNA Origami Cuboids As Monodisperse Patchy Nanoparticles For Switchable Hierarchical Self-Assembly.” November 2016, http://pubs.acs.org/doi/abs/10.1021/acs.nanolett.6b04146
  5. “Toward Larger DNA Origami.” September 2014, http://pubs.acs.org/doi/abs/10.1021/nl502626s
  6. “Nucleic Acid Junctions And Lattices.” November 1982, http://www.sciencedirect.com/science/article/pii/0022519382900029
  7. “Rapid Prototyping Of 3D DNA-Origami Shapes With caDNAno.” May 2009, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731887/pdf/gkp436.pdf
  8. “DNA Rendering Of Polyhedral Meshes At The Nanoscale.” February 2015, https://www.nature.com/nature/journal/v523/n7561/full/nature14586.html