— By Theresa Duque
As a senior scientist and Biological Nanostructures Facility Director at the Lab’s Molecular Foundry, thinking in three dimensions comes naturally to Ron Zuckermann. He is, after all, the lead developer behind the Peppytide protein models, an award-winning 3D hands-on educational tool. When he’s not thinking of fun ways to teach chemistry in 3D, however, Zuckermann and his team of researchers are designing two-dimensional peptoid nanosheets — a material made of biomimetic polymers, two molecules thick — that could one day be used to make sensors that detect lethal chemical agents or deadly viruses deployed during warfare or a terrorist attack.
For the past six years, Zuckermann has been funded by the Defense Threat Reduction Agency (DTRA) of the Department of Defense (DOD) to design synthetic proteins that do all the things a natural antibody protein can do — self-assemble into a precise structure that recognizes viruses and bacteria — but are more durable than natural molecules and can be stored without refrigeration. Self-assembling biomimetic nanostructures (or nanostructures designed to mimic nature) are also highly sought by the military and industry alike for their potential to rapidly make large quantities of affordable yet more rugged materials.
While Zuckermann knew that linking synthetic amino acids would form long chains of peptoids or synthetic proteins, it was still a mystery as to which of the astronomical number of possible peptoid sequences would actually self-assemble into a usable shape. “There’s no precedent for our research. Once you step off the blueprint of proteins and start with synthetic polymers, there are no directions, no rules. We have to start from scratch,” he explains. In 2010, however, years of working in uncharted territory paid off when Zuckermann and his team discovered a unique peptoid sequence that causes the polymer chains to miraculously “line up like floorboards on a hardwood floor,” self-assembling into two-dimensional peptoid nanosheets, which, it turns out, could be the perfect platform for a threat-agent sensor that soldiers could use to detect chemical threats, nerve gases, and even anthrax.
After successfully mimicking the way nature forms proteins by folding up a polymer chain, Zuckermann has partnered with a panoply of researchers, including Steve Whitelam, a theoretical physicist from the Molecular Foundry’s Theory of Nanostructured Materials Facility; Trent Northen of the Lab’s Life Sciences Division; and other notable scientists from UC San Francisco, Pacific Northwest National Laboratory, and New York University, to turn the 2D peptoid nanosheets into a national security device. As part of a $2 million effort funded by the DOD Defense Advanced Research Projects Agency’s Fold F(x) Program, Zuckermann and his team will build the world’s first library of 108 or 100 million different nanosheet “flavors” by adding “loops” of various traits (ranging from big or small, positively or negatively charged, or hydrophilic or hydrophobic, for example) to the nanosheet surface. Each nanosheet flavor — all 100 million of them — will be tested for its effectiveness in detecting and neutralizing threat agents, such as anthrax. (The full duration of the DARPA project is four years. Successful completion of the first year, which began on September 1, could lead to an additional funding of approximately $4 million.)
While some might balk at DARPA’s call for 100 million folded nanostructures, Zuckermann sees it as an opportunity to leverage the Molecular Foundry’s strengths with research universities and Department of Energy national laboratories across the country. “The DARPA program’s vision to produce combinatorial libraries of protein mimics fits nicely with the Foundry’s thematic focus on combinatorial nanoscience, which aims to create many different structural analogs of a synthetic nanomaterial, and to test them all for emergent properties,” he says.
For more information about the development of synthetic proteins to create better materials, go here to watch Zuckermann’s “Eight Big Ideas” talk presented for a Berkeley Lab Science at the Theatre event.