DNA nanotechnology uses DNA molecules as programmable building blocks to create structures with high control
![This protein-DNA system was assembled by a three-armed DNA triangle of complementary strands forming tetrahedral cages consisting of six sides of DNA and a trimeric protein [Courtesy: Nicholas Stephanopoulos]](https://www.hayadan.org.il/images/content3/2019/05/toc_figure_3-11.jpg.webp)
The main purpose of nanotechnology is to change materials at the atomic or molecular level, especially for the development of microscopic devices or structures. XNUMXD cage-type structures are one of the main targets in this field, both due to their simplicity and their use as drug carriers.
At the same time, the structure of DNA is very simple and lacks the diversity of proteins that make up most of the natural cages, for example, in the world of viruses. Unfortunately, it is very challenging to control the aggregation of proteins with the precision of DNA. However, this situation was true until recently. Researcher Nicholas Stephanopoulos, a professor at Arizona State University, and his research team, created a cage consisting of both DNA building blocks and protein building blocks, using protein-DNA covalent conjugates.
In an article published long ago in the scientific journal ACS Nano, the researchers describe how they made changes to a homotrimeric protein (a natural enzyme called KDPG aldolase) while combining it with three identical individual strands of DNA and connecting them through a cysteine amino acid residue to the surface of the protein. This protein-DNA system was connected to a triangular DNA structure that includes three complementary arms to the DNA strands of the system while obtaining tetrahedral cages consisting of six sides of DNA associated with the trimeric protein. The size of the cage can be changed by changing the number of DNA arms. Cage structures were also modified with DNA using click chemistry, which is an adapted type of chemical synthesis, in order to quickly prepare identical structures while connecting together microscopic subunits.
"My lab's approach will enable the synthesis of nanomaterials with advantages of both protein technology and DNA technology, materials that could reach applications in the fields of targeted material transfer, structural biology, biomedicine and catalysis," explains the lead researcher. The researchers see a new opportunity in hybrid cages - a fusion of self-construction of building blocks of proteins together with a synthetic scaffold of DNA - which will be able to combine together the high bioactivity of proteins together with the chemical diversity of DNA. And that's exactly what the researchers did - they created a fused structure consisting of chemical combinations of oligonucleotides (synthetic DNA strand) on protein building blocks. The triple base bearing three arms of single-stranded complementary DNA is obtained by self-construction and undergoes purification by heating.
"We believed that after designing these two purified building blocks, they would simply join together independently in a programmed way, using the identification features of the DNA strands," explains the lead researcher. "It was particularly important to use a protein that is stable at a high temperature, such as this aldolase, since self-assembly is only possible at a temperature of 55 degrees Celsius, while many proteins break down at this temperature." Another advantage of using DNA, which is not possible when using only proteins, is adjusting the size of the cage without redesigning all the other components. The size of the system can be adjusted by changing the length of the DNA arm, while the proteins are used as a scaffold for the connection of small molecules such as targeted peptides or even a chimeric protein.
Although other examples of hybrid structures exist, this cage is the first example obtained through chemical coupling of oligonucleotide arms to protein-type building blocks. In principle, this approach could be applied to a wide variety of proteins (some of which have selective binding capabilities to cancer cells only). Therefore, the current research could enable the development of a completely new hybrid field of protein-DNA nanotechnology that would lead to applications that were not possible until now relying on proteins alone or DNA alone.
