Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
Institute for Quantitative Biomedicine, Rutgers University, Piscataway, NJ, USA.
Nat Chem. 2019 Jul;11(7):605-614. doi: 10.1038/s41557-019-0277-y. Epub 2019 Jun 17.
Fractal topologies, which are statistically self-similar over multiple length scales, are pervasive in nature. The recurrence of patterns in fractal-shaped branched objects, such as trees, lungs and sponges, results in a high surface area to volume ratio, which provides key functional advantages including molecular trapping and exchange. Mimicking these topologies in designed protein-based assemblies could provide access to functional biomaterials. Here we describe a computational design approach for the reversible self-assembly of proteins into tunable supramolecular fractal-like topologies in response to phosphorylation. Guided by atomic-resolution models, we develop fusions of Src homology 2 (SH2) domain or a phosphorylatable SH2-binding peptide, respectively, to two symmetric, homo-oligomeric proteins. Mixing the two designed components resulted in a variety of dendritic, hyperbranched and sponge-like topologies that are phosphorylation-dependent and self-similar over three decades (~10 nm-10 μm) of length scale, in agreement with models from multiscale computational simulations. Designed assemblies perform efficient phosphorylation-dependent capture and release of cargo proteins.
分形拓扑结构在多个长度尺度上具有统计自相似性，广泛存在于自然界中。分形形状的分支物体（如树木、肺部和海绵）中的图案重复出现，导致高的表面积与体积比，这提供了关键的功能优势，包括分子捕获和交换。在设计的基于蛋白质的组装体中模拟这些拓扑结构，可以获得功能性生物材料。在这里，我们描述了一种计算设计方法，用于在响应磷酸化时将蛋白质可逆地自组装成可调谐的超分子分形样拓扑结构。受原子分辨率模型的指导，我们分别将Src 同源 2 (SH2) 结构域或可磷酸化的 SH2 结合肽融合到两个对称的同聚寡聚蛋白上。混合两种设计的成分会导致各种树枝状、超支化和海绵状拓扑结构，这些结构是磷酸化依赖的，并且在三个数量级（~10nm-10μm）的长度尺度上具有自相似性，与多尺度计算模拟的模型一致。设计的组装体能够有效地进行磷酸化依赖的货物蛋白的捕获和释放。
