Hierarchical design of pseudosymmetric protein nanocages

• 成果类型: Article
• 署名作者: Dowling, Quinton M.; Park, Young-Jun; Fries, Chelsea N.; Gerstenmaier, Neil C.; Ols, Sebastian; Yang, Erin C.; Wargacki, Adam J.; Dosey, Annie; Hsia, Yang; Ravichandran, Rashmi; Walkey, Carl D.; Burrell, Anika L.; Veesler, David; Baker, David; King, Neil P.
• 署名单位: University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1934
• DOI: 10.1038/s41586-024-08360-6
• 发表日期: 2025-02-13
• 关键词: neutralizing antibody-responses; nanoparticle vaccine; atomic-structure; symmetry; cages; EVOLUTION; generation; mechanism

摘要

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.