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
Department of Bioengineering, University of Washington, Seattle, WA, USA.
Institute for Protein Design, University of Washington, Seattle, WA, USA.
Nature. 2025 Feb;638(8050):553-561. doi: 10.1038/s41586-024-08360-6. Epub 2024 Dec 18.
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. 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. 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.
大小从数百千道尔顿到数百兆道尔顿不等的离散蛋白质组装体是生物系统中普遍存在的特征，并执行高度专业化的功能。尽管最近在精确设计新的自组装蛋白质方面取得了显著进展，但这些组装体的大小和复杂性一直受到对严格对称性的依赖的限制。在这里，受细菌微区室和病毒衣壳中观察到的假对称性的启发，我们开发了一种分层计算方法，用于设计大型假对称自组装蛋白质纳米材料。我们通过计算设计了假对称异源寡聚体成分，并使用它们来创建具有二十面体对称性的离散笼状蛋白质组装体，其中包含240、540和960个亚基。这些纳米笼的直径分别为49、71和96纳米，是迄今为止通过计算设计生成的最大的有界蛋白质组装体。更广泛地说，通过超越严格的对称性，我们的工作大大拓宽了通过设计可获得的自组装蛋白质结构的种类。
