Hierarchical design of pseudosymmetric protein nanocages

Quinton M. Dowling, Young-Jun Park, Chelsea N. Fries, Neil C. Gerstenmaier, Sebastian Ols, Erin C. Yang, Adam J. Wargacki, Annie Dosey, Yang Hsia, Rashmi Ravichandran, Carl D. Walkey, Anika L. Burrell, David Veesler, David Baker and Neil P. King ()
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Quinton M. Dowling: University of Washington
Young-Jun Park: University of Washington
Chelsea N. Fries: University of Washington
Neil C. Gerstenmaier: University of Washington
Sebastian Ols: University of Washington
Erin C. Yang: University of Washington
Adam J. Wargacki: University of Washington
Annie Dosey: University of Washington
Yang Hsia: University of Washington
Rashmi Ravichandran: University of Washington
Carl D. Walkey: University of Washington
Anika L. Burrell: University of Washington
David Veesler: University of Washington
David Baker: University of Washington
Neil P. King: University of Washington

Nature, 2025, vol. 638, issue 8050, 553-561

Abstract: Abstract Discrete protein assemblies ranging from hundreds of kilodaltons to hundreds of megadaltons in size are a ubiquitous feature of biological systems and perform highly specialized functions1,2. Despite remarkable recent progress in accurately designing new self-assembling proteins, the size and complexity of these assemblies has been limited by a reliance on strict symmetry3. Here, inspired by the pseudosymmetry observed in bacterial microcompartments and viral capsids, we developed a hierarchical computational method for designing large pseudosymmetric self-assembling protein nanomaterials. We computationally designed pseudosymmetric heterooligomeric components and used them to create discrete, cage-like protein assemblies with icosahedral symmetry containing 240, 540 and 960 subunits. At 49, 71 and 96 nm diameter, these nanocages are the largest bounded computationally designed protein assemblies generated to date. More broadly, by moving beyond strict symmetry, our work substantially broadens the variety of self-assembling protein architectures that are accessible through design.

Date: 2025
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DOI: 10.1038/s41586-024-08360-6

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