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.
Bibliographical noteFunding Information:
The authors acknowledge support from the NSF (1330760 to S.D.K. and L.W.; DGE-1433187 to N.E.H.; 1429062 to S.D.K.) and the NIH (R01GM080139 to M.C.). Cryoelectron microscopy was supported by the Rutgers New Jersey CryoEM/ET Core Facility. The authors thank J. Chodera for providing Src kinase and YopH phosphatase plasmids, V. Nanda, K.-B. Lee, G. Montelione, H. Cho, M. Liu, A. Permaul, O. Dineen, I. Patel and R. Patel for experimental assistance, and E. Tinberg, V. Nanda and D. Baker for helpful discussions.