Bad bacteria can survive in extremely hostile environments — including inside the highly acidic human stomach — thanks to their ability to sequester toxins into tiny compartments.
In a new study, Northwestern University researchers have, for the first time, theoretically and experimentally controlled protein assembly to build these microcompartments into different shapes and sizes, including long tubes and polyhedra. Not only does this work illuminate how biological units, such as viruses and organelles, develop, it also could inform new ways to design medicine, synthetic cells and nanoreactors.
Further down the road, these insights potentially could lead to new antibiotics that target microcompartments of pathogens while sparing good bacteria.
“By carefully designing proteins to have specific mutations, we were able to control assembly of the proteins that form bacterial microcompartments,” said Northwestern’s Monica Olvera de la Cruz, who led the theoretical computation. “We used this also to predict other possible formations that have not yet been observed in nature.”
“Based on previous observations, we have known that the geometry of microcompartments can be altered,” added Danielle Tullman-Ercek, who led the experimental work. “But our work provides the first clues into how to alter them to achieve specific shapes and sizes.”
Olvera de la Cruz is the Lawyer Taylor Professor of Materials Science and Engineering at Northwestern’s McCormick School of Engineering. Tullman-Ercek is an associate professor of chemical and biological engineering at McCormick.
The research is featured in the April issue of ACS Central Science, which published today (April 28).
“These results are an exciting step forward in our ability to design complex protein-based components,” said Dr. Stephanie McElhinny, program manager at the Army Research Office, a part of the U.S. Army Combat Capabilities Development Command’s Army Research Laboratory, which supported the experimental component of the research. “Being able to control the size and shape of these components could enable sophisticated biomanufacturing schemes that are customized to support efficient production of complex molecules and multi-functional materials that could provide the future Army with enhanced uniforms, protective equipment and environmental sensors.”
Many cells use compartmentalization to ensure that various biochemical processes can occur simultaneously without interfering with one another. Made of proteins, these microcompartments are a key to survival for a wide variety of bacterial species.
To study these crucial compartments, the Northwestern team turned to Salmonella enterica, which rely on microcompartments to break down the waste products of good bacteria in the gut. When the researchers genetically manipulated a protein isolated from Salmonella, they noticed the microcompartments formed long tubes.
“We saw these weird, extended structures,” Tullman-Ercek said. “It looked like they used the varying building blocks to form different shapes with different properties.”
By coupling the mechanical properties of the compartment with the chemicals inside the compartment, Olvera de la Cruz and her team used theoretical computation to predict how different mutations led to different shapes and sizes. When six-sided proteins assembled together, they formed long tubes. When five-sided proteins assembled together, they formed soccer ball-shaped icosahedrons. The team also predicted that proteins could assemble into a triangular “samosa” shape, resembling the fried, South Asian snack.
Understanding this process could lead to bio-inspired building blocks for various engineering applications that require components of varying shapes and sizes.
“It’s like building with Legos,” Tullman-Ercek said. “It’s not desirable to use the same shape block over and over again; we need different shapes Learning from bacteria can help us build new and better structures at this microscopic scale.”
The study, “Computational and experimental approaches to controlling bacterial microcompartment assembly,” was supported by the Army Research Office (award number W911NF-19-1-0298), Department of Energy (award number DE-FG02-08ER46539), the National Science Foundation and the Sherman Fairchild Foundation.
