Stimulus-responsive self-assembly of protein-based fractals by computational design

Nancy E. Hernández, William A. Hansen, Denzel Zhu, Maria E. Shea, Marium Khalid, Viacheslav Manichev, Matthew Putnins, Muyuan Chen, Anthony G. Dodge, Lu Yang, Ileana Marrero-Berríos, Melissa Banal, Phillip Rechani, Torgny Gustafsson, Leonard C. Feldman, Sang Hyuk Lee, Lawrence P. Wackett, Wei Dai, Sagar D. Khare

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)605-614
Number of pages10
JournalNature Chemistry
Issue number7
StatePublished - Jul 1 2019

Bibliographical note

Funding 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.


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