Hierarchical design of pseudosymmetric protein nanocages

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 functions<sup>1,2</sup>. 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 symmetry<sup>3</sup>. 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.

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Publication Details

Journal
Nature
Published
2024-12-18
DOI
https://doi.org/10.1038/s41586-024-08360-6
Citations
34
Primary Topic
Bacteriophages and microbial interactions
Type
article
Field-Weighted Citation Impact
15.60

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article

Hierarchical design of pseudosymmetric protein nanocages

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Hierarchical design of pseudosymmetric protein nanocages

Adam J. Wargacki, Erin C. Yang, Neil P. King, Sebastian Ols, Rashmi Ravichandran, Yang Hsia, Carl Walkey, Young‐Jun Park, David A. Baker, Annie Dosey, Anika L. Burrell, Quinton M. Dowling, David Veesler, Chelsea N. Fries, Neil Gerstenmaier
article en
34 citations

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 functions<sup>1,2</sup>. 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 symmetry<sup>3</sup>. 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.

NatureVol. 638(8050)
Howard Hughes Medical Institute (US), University of Washington (US)
National Science Foundation, Bill and Melinda Gates Foundation, Ohio State University, University of Washington, Open Philanthropy Project, National Institutes of Health
Openalex Percentile: Top 1%
Bacteriophages and microbial interactions
15.60
DOIOpen Access PDFOpenAlex
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