华盛顿大学David Baker小组的一项最新研究开发出单组分准对称蛋白质纳米笼的设计。2026年5月20日出版的《自然》杂志发表了这项成果。

在这里，课题组推测准对称可能是由具有编程曲率的强相互作用的构建块系统中的自发对称性破缺引起的，并表明这一原理，加上将笼子结构的参数化表示与RoseTTAFold扩散生成建模相结合的设计方法，可以生成丰富的准对称组件阵列。电子显微镜证实了所设计的具有180至2160个亚基、直径在68纳米至220纳米之间的3≤T≤36笼状结构，以及所设计的1<T<3非二十面体网格蛋白样组装体的结构。低温电子显微镜结构测定揭示了T=3结构中六邻体和五邻体形成相关的全局对称性破缺是如何源于设计亚基界面中的对称性破缺的。他们的研究结果表明，如何通过设计整体系统属性来控制复杂系统的详细架构，他们的方法为设计用于生物制剂输送和其他应用的大型准对称组件提供了路线图。

据介绍，虽然单个构建块可以构建的最大的完全对称封闭组装体是60个亚基的二十面体，但虚拟主题可以通过准对称-将相同的亚基在组装体的对称非等效位置上进行主题化，形成具有数百到16个相同亚基的衣壳组装体。准对称的单组分组件对于生物制剂的输送具有相当大的优势，因为只有一个构建块可以实现大的内部体积，但是这些结构的设计是具有挑战性的，因为设计化学相同的亚基在不同的对称非等效位置采用不同的构象和不同的相互作用具有固有的复杂性。

附：英文原文

Title: Design of one-component quasisymmetric protein nanocages

Author: Lee, Sangmin, Chmielewski, David, Wang, Shunzhi, Kibler, Ryan D., Shin, Jisu, Carr, Ann, Park, Young-Jun, Veesler, David, Baker, David

Issue&Volume: 2026-05-20

Abstract: Although the largest completely symmetric closed assembly that can be built from a single building block is the 60-subunit icosahedron1, viruses can form capsid assemblies with hundreds to thousands of identical subunits through quasisymmetry—using the same subunit in symmetrically non-equivalent locations in the assembly2,3,4,5. Quasisymmetric one-component assemblies could have considerable advantages for delivery of biologics because of the large internal volume achieved using only a single building block, but the design of these structures is challenging because of the inherent complexity of designing chemically identical subunits to both adopt different conformations and make different interactions in the distinct symmetrically non-equivalent locations. Here we conjectured that quasisymmetry could arise from spontaneous symmetry breaking in a system of strongly interacting building blocks with programmed curvatures and show that this principle, coupled with a design approach combining a parametric representation of cage architecture with RoseTTAFold diffusion generative modelling, can generate a rich array of quasisymmetric assemblies. Electron microscopy confirmed the structures of designed 3≤T≤36 cages with 180–2,160 subunits and diameters from 68nm to 220nm, and designed 1<T<3 non-icosahedral clathrin-like assemblies. Cryogenic electron microscopy structure determination showed how the global symmetry breaking associated with the formation of both hexons and pentons in the T=3 architecture arises from symmetry breaking in the designed subunit interface. Our results indicate how the detailed architecture of complex systems can be controlled by designing overall system properties, and our approach provides a roadmap for designing large quasisymmetric assemblies for biologics delivery and other applications.

DOI: 10.1038/s41586-026-10554-z

Source: https://www.nature.com/articles/s41586-026-10554-z