华盛顿大学David Baker小组在研究中取得进展。他们提出了准对称双组分蛋白质笼的从头设计。2026年5月20日，国际知名学术期刊《自然》发表了这一成果。

在这里，课题组人员介绍了一种基于几何热沉的计算设计策略，以生成具有可自构性的双组分准对称蛋白质笼。该团队设计了互补的三聚体和二聚体蛋白质组件，共同组装成正弯曲的局部六边形组件。六边形晶格不能贴球面；相反，通过结合曲率诱导五边形缺陷，组件形成封闭的球形笼组件，如电子显微镜所证明的那样。通过设计编码不同局部曲率的二聚体，编程实现了直径范围从40到超过200纳米、分子量从2百万道尔顿到超过50百万道尔顿的衣壳尺寸，与天然病毒衣壳相当。

研究组用额外的蛋白质结构域进一步功能化这些大笼子，使核糖核蛋白货物装载和细胞摄取成为可能。在哺乳动物细胞中表达的荧光标记的笼子组件具有流变探针和货物招募者的功能，能够系统地研究大小依赖的细胞质扩散和蛋白质定位。因此，长期以来让结构生物学家着迷的准对称性现在可以通过计算蛋白质设计来实现，并立即应用于生物制剂传递和分子细胞生物学。

据悉，准对称二十面体病毒衣壳比严格对称二十面体的衣壳尺寸更大，方法是将五边形和六边形围绕一个在对称非等效位置采用不同构象的亚基进行细分。在纳米材料工程中，通过计算设计来重现这种准对称结构是一个相当大的挑战。

附：英文原文

Title: De novo design of quasisymmetric two-component protein cages

Author: Wang, Shunzhi, Xie, Ying, Chemielewski, David, Weidle, Connor, Shu, Tong, Ahn, Green, Kibler, Ryan D., Hernandez, Cindy, Chen, Wei, Duran, David Camilo, Carr, Ann, Bera, Asim K., Lee, Sangmin, Decarreau, Justin, Kang, Alex, Brackenbrough, Evans, Joyce, Emily, Wu, Kejia, Borst, Andrew J., Favor, Andrew, Huang, Buwei, DiMaio, Frank, Holt, Liam J., Baker, David

Issue&Volume: 2026-05-20

Abstract: Quasisymmetric icosahedral viral capsids achieve larger sizes than possible with strictly symmetric icosahedra by tessellating pentagons and hexagons using a single subunit that adopts different conformations in symmetrically non-equivalent locations1,2. Recapitulating such quasisymmetric architectures through computational design is a considerable challenge in nanomaterials engineering. Here we introduce a computational design strategy based on geometric frustration to generate two-component, quasisymmetric protein cages with customizable properties. We designed complementary trimeric and dimeric protein components that co-assemble into positively curved local hexagonal assemblies. Hexagonal lattices cannot tile spherical surfaces; instead, the components form closed sphere-like cage assemblies through incorporation of curvature-inducing pentagonal defects, as evidenced by electron microscopy. By designing dimers that encode different local curvatures, we programmed cage dimensions ranging from 40 to over 200nm in diameter and with molecular weights from 2MDa to over 50MDa, comparable with natural virus capsids. We further functionalized these large cages with additional protein domains to enable ribonucleoprotein cargo loading and cellular uptake. Fluorescently labelled cage assemblies expressed in mammalian cells function as rheological probes and cargo recruiters, enabling a systematic study of size-dependent cytoplasmic diffusion and protein localization. Thus, the quasi-symmetry that has long fascinated structural biologists can now be achieved by computational protein design, with immediate applications to biologics delivery and molecular cell biology.

DOI: 10.1038/s41586-026-10464-0

Source: https://www.nature.com/articles/s41586-026-10464-0