In work published recently in Nature Structural & Mechanical Biology, scientists at Fred Hutchinson Cancer Research Center described self-assembling, donut-shaped protein nanoparticles designed from scratch. The team showed that the nanoparticles, which can act as scaffolds for the organization and display of biomolecules currently used in various clinical and research applications, could someday enhance these applications by simplifying biomolecule production or by enabling scientists to introduce entirely new biomolecules.

“We have developed a novel molecular scaffold that can display many copies of different types of cool proteins in a variety of numbers and organizations,” said Dr. Colin Correnti, a Hutch protein scientist who spearheaded the efforts to make the circular proteins self-assemble and to test drive potential uses of the scaffolds. Correnti joined the protein scaffolds’ original engineers, Hutch computational biologist Dr. Phil Bradley and Hutch structural biologist Dr. Barry Stoddard, to form a centerwide, interdisciplinary team. 

The engineered molecular scaffolds, made up of a repeated protein motif, are called circular tandem-repeat proteins, or cTRPs. In the latest study, the team showed they could create large cTRPs that self-assemble by breaking them into six repeat-long modules with molecular “staples” on both ends. To demonstrate a real-world application, the team attached various proteins that are used in the study and manufacture of engineered anti-cancer immune cells. They showed that using the cTRPs instead of the standard molecular tool could potentially help streamline immunotherapy production — just one of the many applications the team envisions for their nano-circle scaffolds.

“We’ve basically created an endless idea-generation machine,” Correnti said. “Any biomolecule that you want to click on to a cTRP particle, you can. Really, there's not another platform out there that allows you to do that.”

The team's cTRPs can also be produced in mammalian cells rather than bacterial cells, which widens the scope of potential cargo options (as well as simplifying their production). One application has been licensed to a biotech company.

Though now poised for use in real-world applications, the self-assembling cTRPs that Bradley, Stoddard and Correnti developed sprung from basic curiosity about proteins and the relationship between their amino acid sequence and their final form. Several years ago, Bradley was developing computational methods to predict the structure of a naturally occurring TRP while Stoddard was working to visualize its structure directly.

“This all started out because Phil was fundamentally interested in whether he could predict the structure, or even actually design a particularly interesting type of folded protein,” Stoddard said. “It could not have been more a basic and curiosity-driven project.”

Why design a custom protein? You may need it to perform a function that doesn’t exist in nature.

“Designed proteins can often be, in some way, superior to naturally occurring proteins unless the naturally occurring protein already does what you want done,” Bradley said. And because protein designers can choose the most ideal characteristics for their proteins, designed proteins are often very stable and easily produced by cells.

Bradley realized he could adapt the computational tools he was developing to predict structure to design his own TRP. Stoddard jumped at the chance to put Bradley’s principles into practice and test how closely such an engineered protein would adhere to the structure predicted on the computer.

They choose to design circular proteins because of their natural stability and symmetry. In 2015, Bradley and Stoddard demonstrated that they could indeed design circular proteins out of repeating subunits, and they published the work in the journal Nature. Next, they wanted to refine the approach and begin moving toward practical applications.

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