June 5, 2014

King, N.P., Bale, J.B., Sheffler, W., et al. (2014). Accurate design of co-assembling multi-component protein nanomaterials. Nature. 510, 103-108.

Scientists at the Institute for Protein Design (IPD), in collaboration with researchers at UCLA and HHMI, can now design and build self-assembling protein nanomaterials made up of multiple components with near atomic-level accuracy.

 The protein nanoparticle design team. From left to right: graduate student Stephanie Berger, graduate student Jacob Bale, IPD translational investigator Dr. Neil King, senior fellow Dr. Jorge Fallas, and senior fellow Dr. Will Sheffler.
The protein nanoparticle design team. From left to right: graduate student Stephanie Berger, graduate student Jacob Bale, IPD translational investigator Dr. Neil King, senior fellow Dr. Jorge Fallas, and senior fellow Dr. Will Sheffler. Jacob Bale, Dr. King and Dr. Sheffler contributed to the work described in the 2014 Nature paper.


A previously published 2012 Science paper described a new computational method for the design of protein building blocks that self-assemble to a desired symmetric architecture. The general conceptual approach for this protein nanomaterial design consists of two steps: docking of protein building blocks on defined symmetric axes followed by design of low energy protein-protein interfaces between the building blocks (to drive self-assembly) (Figure 1). With this computational method, King et al designed single-component protein nanomaterials that self-assemble into octahedral and tetrahedral symmetric cage-like complexes. The designed protein crystal structures fit the computational predictions within one angstrom, demonstrating the exceptional accuracy of the computational design method.

Self Assembling Nanomaterials
Figure 1. Single-component self-assembling protein nanomaterials

In a Nature paper published this week entitled Accurate design of co-assembling multi-component protein nanomaterials, IPD translational investigator Dr. Neil King, Baker lab graduate student Jacob Bale, Baker lab senior fellow Will Sheffler and collaborators (see picture above) take this work to the next step: design of protein assemblies that are made up of two distinct components (Figure 2).

This time, Rosetta computational design software capabilities were expanded to model multiple different protein building blocks at the same time. Two different sets of building blocks are docked along symmetry axes to identify large interfaces between subunits that have high densities of contacting residues. The sequences at the interfaces are redesigned to stabilize the interaction and to drive co-assembly of the two sets of protein building blocks. Individually expressed protein building blocks can be mixed together to initiate nanoparticle assembly. Once again, x-ray crystal structures demonstrated that the protein structures are in very high agreement with the design models. The computational method is generalizable to produce a number of different symmetrical architectures composed of distinct protein subunits in various arrangements.

Figure 2. Computational design models (top) and crystal structures (bottom) are shown for two different designed two-component protein nanomaterials, both with tetrahedral symmetry. Overlays show the strong agreement between design model (white) and crystal structure (orange/grey, green/blue).

Why is this important?

Protein self-assembly plays a critical role in many biological processes (e.g. viruses self-assemble into complexes that encase, protect and deliver viral DNA to a host cell). Efforts to make novel self-assembling materials have seen success with DNA and RNA (see DNA origami), but attempts to design self-assembling protein structures that would have greater functional and structural properties have been challenging to date. Protein nanomaterials, such as the ones described in the two papers mentioned above, have potential applications in vaccine design, targeted drug delivery, imaging agents and new biomaterials. Multi-component self-assembling systems offer a number of advantages including a wider range of modular protein architectures. Furthermore, complexes requiring two or more components to assemble allow for increased control over the timing of cage assembly.

What’s next?

Work is ongoing at the IPD to begin functionalizing these protein nanomaterials for various applications. Furthermore, to expand the scope of the protein nanocages with tunable properties and varying sizes and structures, the next step would be to design self-assembling protein nanomaterials composed of de novo designed building blocks, i.e. ones not based on scaffolds that already exist in nature.

Two-component cage. Illustration rendered by Vikram K. Mulligan.

Additional press coverage

University of Washington News ran a story entitled Self-assembling nanomachines start to click. This UW News story is featured in the U.S. Department of Energy’s Science Headlines section on their homepage and at www.sciencedaily.com.