Rankovic Sanela, Carr Kenneth D, Decarreau Justin, Skotheim Rebecca, Kibler Ryan D, Ols Sebastian, Lee Sangmin, Chun Jung-Ho, Tooley Marti R, Dauparas Justas, Eisenach Helen E, Glögl Matthias, Weidle Connor, Borst Andrew J, Baker David, King Neil P
Department of Biochemistry, University of Washington, Seattle, WA, USA.
Institute for Protein Design, University of Washington, Seattle, WA, USA.
Nat Mater. 2025 Jul 31. doi: 10.1038/s41563-025-02295-7.
Advances in computational methods have led to considerable progress in the design of protein nanomaterials. However, nearly all nanoparticles designed so far exhibit strict point group symmetry, which limits structural diversity and precludes anisotropic functionalization. Here we describe a computational strategy for designing multicomponent bifaceted protein nanomaterials with two distinctly addressable sides. The method centres on docking pseudosymmetric hetero-oligomeric building blocks in architectures with dihedral symmetry and designing an asymmetric protein-protein interface between them. We obtain an initial 30-subunit assembly with pseudo-D symmetry and generate variants in which we alter the size and morphology of the bifaceted nanoparticles by designing extensions to one of the subunits. Functionalization of the two nanoparticle faces with protein minibinders enables the specific colocalization of two populations of polystyrene microparticles coated with the target protein receptors. The ability to accurately design anisotropic protein nanoparticles could be broadly useful in applications requiring the colocalization of distinct target moieties.
计算方法的进步推动了蛋白质纳米材料设计的显著进展。然而，迄今为止设计的几乎所有纳米颗粒都表现出严格的点群对称性，这限制了结构多样性并排除了各向异性功能化。在此，我们描述了一种用于设计具有两个可明确寻址面的多组分双面包蛋白质纳米材料的计算策略。该方法的核心是将伪对称异源寡聚构建块对接在具有二面角对称性的结构中，并在它们之间设计一个不对称的蛋白质-蛋白质界面。我们获得了一个具有伪D对称性的初始30亚基组装体，并通过设计其中一个亚基的延伸部分来生成变体，从而改变双面包纳米颗粒的大小和形态。用蛋白质微型结合剂对纳米颗粒的两个面进行功能化，能够使涂有靶蛋白受体的两种聚苯乙烯微粒群体进行特异性共定位。精确设计各向异性蛋白质纳米颗粒的能力在需要不同靶标部分共定位的应用中可能具有广泛的用途。
