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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • Algorithms
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Escherichia coli / chemistry
  • Fractals*
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Phosphorylation
  • Protein Aggregates*
  • Protein Engineering / methods
  • Protein Multimerization
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • src Homology Domains / genetics
  • src-Family Kinases / metabolism


  • Bacterial Proteins
  • Protein Aggregates
  • Recombinant Fusion Proteins
  • src-Family Kinases