Image showing stages in the synthesis of a nanowire made from DNA and protein. Image: Yun (Kurt) Mou, Jiun-Yann Yu, Timothy M. Wannier, Chin-Lin Guo and Stephen L. Mayo/Caltech.
Image showing stages in the synthesis of a nanowire made from DNA and protein. Image: Yun (Kurt) Mou, Jiun-Yann Yu, Timothy M. Wannier, Chin-Lin Guo and Stephen L. Mayo/Caltech.

Over the past few years, scientists have become adept at making synthetic structures from DNA or protein alone. Now a team from the California Institute of Technology (Caltech) has gone one stage further, by becoming the first to create a synthetic structure made of both protein and DNA. Combining the two molecule types into one biomaterial opens the door to numerous applications.

There are many advantages to multiple component materials, says Yun (Kurt) Mou, first author of a paper describing the so-called hybridized, or multiple component, material in Nature. "If your material is made up of several different kinds of components, it can have more functionality. For example, protein is very versatile; it can be used for many things, such as protein-protein interactions or as an enzyme to speed up a reaction. And DNA is easily programmed into nanostructures of a variety of sizes and shapes."

But how do you begin to create something like a protein-DNA nanowire – a material that no one has seen before?

Mou and his colleagues in the laboratory of Stephen Mayo, professor of biology and chemistry in Caltech's Division of Biology and Biological Engineering, started by using a computer program to design the type of protein and DNA that would work best as part of their hybrid material. "Materials can be formed using just a trial-and-error method of combining things to see what results, but it's better and more efficient if you can first predict what the structure is like and then design a protein to form that kind of material," he says.

The researchers entered the properties of the protein-DNA nanowire they wanted into a computer program developed in the lab. The program then generated a sequence of amino acids and nitrogenous bases that would produce the desired material.

Although the computer model can come up with a sequence, the researchers then need to check the model thoroughly to be sure that the sequence makes sense; if not, the researchers must provide the computer with information that can be used to correct the model. "So in the end, you choose the sequence that you and the computer both agree on,” Mou explains. “Then, you can physically mix the prescribed amino acids and DNA bases to form the nanowire."

In this case, the resulting sequence utilized an artificial version of a protein-DNA coupling that occurs in nature, during the initial stage of gene expression, called transcription, when a sequence of DNA is first converted into RNA. To begin the process of transcribing the DNA into RNA, proteins called transcription factors must first bind to specific regions of the DNA sequence known as protein-binding domains.

Using the computer program, the researchers engineered a sequence of DNA that contained many of these protein-binding domains at regular intervals. They then selected the transcription factor that naturally binds to this particular protein-binding site – a transcription factor called Engrailed derived from the fruit fly Drosophila.

In nature, Engrailed attaches itself solely to the protein-binding site on the DNA. To create a long nanowire made of a continuous strand of protein attached to a continuous strand of DNA, however, the researchers had to modify the transcription factor to include a site that would allow Engrailed to bind to the next protein in line as well.

"Essentially, it's like giving this protein two hands instead of just one," Mou explains. "The hand that holds the DNA is easy because it is provided by nature, but the other hand needs to be added there to hold onto another protein."

Another unique attribute of this new protein-DNA nanowire is that it employs co-assembly, meaning that the material will not form until both the protein components and the DNA components have been added to the solution. Although scientists have already made materials from DNA with protein added later, the use of co-assembly to make the hybrid material was a first. This attribute is important for the material's future use in medicine or industry, Mou says, as the two sets of components can be provided separately and then combined to make the nanowire whenever and wherever it is needed.

This study builds on earlier work in the Mayo lab, which, in 1997, created one of the first artificial proteins, thus launching the field of computational protein design. The ability to create synthetic proteins allows researchers to design and develop proteins with new capabilities and functions, such as therapeutic proteins that target cancer. The creation of a co-assembled protein-DNA nanowire is another milestone in this field.

"Our earlier work focused primarily on designing soluble, protein-only systems. The work reported here represents a significant expansion of our activities into the realm of nanoscale mixed biomaterials," Mayo says.

Although the development of this new biomaterial is in the very early stages, the method has many promising applications that could change research and clinical practices in the future. "Our next step will be to explore the many potential applications of our new biomaterial," Mou says. "It could be incorporated into methods to deliver drugs into cells – to create targeted therapies that only bind to a certain biomarker on a certain cell type, such as cancer cells. We could also expand the idea of protein-DNA nanowires to protein-RNA nanowires that could be used for gene therapy applications. And because this material is brand-new, there are probably many more applications that we haven't even considered yet."

This story is adapted from material from Caltech, with editorial changes made by Materials Today. The views expressed in this article do not necessarily represent those of Elsevier. Link to original source.