Expanding DNA nanotech alphabet

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Today, we are looking at an expanded DNA alphabet and its role in DNA nanotech.

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Expanding DNA nanotech alphabet

We all know the basics of DNA: it’s formed by four letters, or nucleotides that pair predictably (A with T and C with G) to store genetic information. This predictability gives DNA a versatility that allows an incredible amount of applications beyond genetics. It’s the foundation for advances in synthetic biology, drug development, and nanoscale structures. But there are limits to what we can do with just four letters: for example, last week we saw that storing larger amounts of data in DNA has proven tricky with just A, T, C, and G.

Scientists saw this limitation early on, and over time, they developed synthetic nucleotides to expand the DNA alphabet. The latest research uses an “hachimoji” system (from the Japanese words “hachi,” meaning eight, and “moji,” meaning letter), which adds four new bases: Z, P, B, and S. In this expanded system, Z pairs with P, and B pairs with S, following the same Watson-Crick hydrogen-bonding rules as natural DNA. Even better, these synthetic bases work well with natural DNA and RNA polymerases, so they’re compatible with cellular processes!

But what’s the point of all these new letters? These additional bases allow scientists to create orthogonal genetic systems—synthetic systems that function independently from the cell’s native DNA. This is huge for gene therapy, biomolecular computing, and synthetic biology because it allows engineered genes or circuits to operate without interfering with the host’s genome. This independence minimizes risks in therapeutic applications and enables safer and more flexible platforms for genetic engineering.

All of this brings us to today’s paper: the researchers explored whether these synthetic bases could be used to create DNA nanomaterials (of course). Specifically, they zeroed in on the Z base pair, which behaves similarly to natural DNA pairs, even showing high compatibility with existing polymerases and natural DNA’s flexibility.

So, how did they test this? The team used a tensegrity triangle, a DNA motif known for self-assembling into stable 3D crystal lattices. Each triangle has sticky ends that connect with neighboring triangles, allowing them to build a larger crystal lattice. The researchers incorporated Z pairs into these sticky ends to see if they could form crystals alongside natural DNA bases.

A unique feature of the Z nucleotide is its natural green fluorescence, which helped the team confirm that the synthetic bases were incorporated properly. Once the crystals formed, they used X-ray diffraction to analyze how the Z pairs interacted within the DNA lattice. The results were promising: the Z pairs integrated seamlessly, maintaining the stable 3D structure expected of the tensegrity triangle motif.

This is exciting because it shows that synthetic base pairs like Z can be incorporated into DNA nanotechnology without needing entirely new tools. This opens up some powerful possibilities:

• Enhanced Drug Delivery: DNA structures with synthetic bases could resist breakdown by nucleases, a challenge in drug delivery.

• Added Chemical Functionalities: New chemical groups could be added to these synthetic bases for specialized interactions or drug-binding sites.

• Advanced Biosensing: The natural fluorescence of Z, for example, could be used to create sensitive, real-time biosensors.

In short, this expanded DNA alphabet offers a pathway to more complex and robust DNA-based nanotechnologies with a wide range of applications! They also provide a great overview of previous applications of the extended DNA base system, so go read the paper here!

In other news:

• Not enough DNA data storage? Then go and check out this awesome review. This review highlights advances in DNA computing and data storage, showcasing DNA's potential in compact, non-traditional environments. It focuses on neural networks, compartmentalized DNA circuits, and processes for writing, reading, and editing DNA-stored data. Looks cool!

• Mapping elements with cryo-EM: This study presents REEL analysis, a method combining electron energy-loss spectroscopy with cryo-EM to enable 3D elemental mapping in cryo-preserved macromolecular structures. REEL reliably localizes elements within sensitive biological samples, helping accurately assign crucial molecules like metals and ions. Very useful stuff.

• Single particle RNA folding: If RNA is more of your jam, you will want to check out this study, which uses individual-particle cryo-electron tomography (IPET) to examine the self-folding of RNA origami. By reconstructing 3D maps of 120 particles, it reveals unique RNA structures and intermediate folding states, suggesting a maturation landscape driven by helix compaction. Pretty cool.

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