Accurate design of megadalton-scale two-component icosahedral protein complexes

By J. Bale, S. Gonen, Yuxi Liu, W. Sheffler, Daniel Ellis, C. Thomas, D. Cascio, Todd O. Yeates, Tamir Gonen, Neil P. King and 1 more. 2016

524 citations recorded by the source corpus.

Designed to assemble Symmetric macromolecular structures that form cages, such as viral capsids, have inspired protein engineering. Bale et al. used pairwise combinations of dimeric, trimeric, or pentameric building blocks to design two-component, 120-subunit protein complexes with three distinct icosahedral architectures. The capsid-like nanostructures are large enough to hold nucleic acids or other proteins, and because they have two components, the assembly of cargoes such as drugs and vaccines can be done in a controlled way. Science, this issue p. 389 A computational approach helped in the design of 120-subunit icosahedral protein cages capable of packaging macromolecular cargo. Nature provides many examples of self- and co-assembling protein-based molecular machines, including icosahedral protein cages that serve as scaffolds, enzymes, and compartments for essential biochemical reactions and icosahedral virus capsids, which encapsidate and protect viral genomes and mediate entry into host cells. Inspired by these natural materials, we report the computational design and experimental characterization of co-assembling, two-component, 120-subunit icosahedral protein nanostructures with molecular weights (1.8 to 2.8 megadaltons) and dimensions (24 to 40 nanometers in diameter) comparable to those of small viral capsids. Electron microscopy, small-angle x-ray scattering, and x-ray crystallography show that 10 designs spanning three distinct icosahedral architectures form materials closely matching the design models. In vitro assembly of icosahedral complexes from independently purified components occurs rapidly, at rates comparable to those of viral capsids, and enables controlled packaging of molecular cargo through charge complementarity. The ability to design megadalton-scale materials with atomic-level accuracy and controllable assembly opens the door to a new generation of genetically programmable protein-based molecular machines.

Subfields: Ecology, Molecular Biology, Computational Biology & Bioinformatics, AI for Physical Sciences

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Citations in the corpus

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, positive): “To overcome the limited immunogenicity of this small, monomeric antigen, we multivalently displayed the RBD on the exterior surface of the twocomponent protein nanoparticle I53-50 (Bale et al., 2016).”
Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, methodology): “The ability to design new self-assembling protein complexes with atomic-level accuracy enables the production of materials with structural features tailored to specific applications (Bale et al., 2016; Hsia et al., 2016; King et al., 2012, 2014).”
The coming of age of de novo protein design (2016, methodology): “Protein interface design methods have been used to create one-or two-component assemblies with icosohedral symmetry and 60 subunits 82 or 120 subunits 83 , respectively.”
Hallucinating protein assemblies (2022, background): “…in advance, and with the exception of parametrically designed helical bundles ( 11 , 12 ), have involved rigid body docking of previously characterized monomers into higher order symmetric structures followed by interface optimization to confer low energy to the assembled state ( 13 – 17 ).”
Essentials of de novo protein design: Methods and applications (2018, background): “12 – 14 However, the dependence on natural proteins for engineering new functions imposes a range of limitations.”
Generative Models for Graph-Based Protein Design (2019, background): “This ﬁeld has seen tremendous progess in the past two decades [1], including the design of novel 3D folds [2], enzymes [3], and complexes [4].”
De novo protein design, a retrospective (2020, methodology): “This method has been used to create novel cages with varying symmetries including icosahedral assemblies (King et al., 2012; Bale et al., 2016; Hsia et al., 2016).”