Accurate design of coassembling multi-component protein nanomaterials

By Neil P. King, J. Bale, W. Sheffler, D. McNamara, S. Gonen, Tamir Gonen, Todd O. Yeates, David Baker. 2014

518 citations recorded by the source corpus.

The self-assembly of proteins into highly ordered nanoscale architectures is a hallmark of biological systems. The sophisticated functions of these molecular machines have inspired the development of methods to engineer self-assembling protein nanostructures; however, the design of multi-component protein nanomaterials with high accuracy remains an outstanding challenge. Here we report a computational method for designing protein nanomaterials in which multiple copies of two distinct subunits co-assemble into a specific architecture. We use the method to design five 24-subunit cage-like protein nanomaterials in two distinct symmetric architectures and experimentally demonstrate that their structures are in close agreement with the computational design models. The accuracy of the method and the number and variety of two-component materials that it makes accessible suggest a route to the construction of functional protein nanomaterials tailored to specific applications.

Subfields: Ecology, Materials Chemistry, Molecular Biology, Computational Chemistry & Drug Discovery

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Citations in the corpus

Robust deep learning based protein sequence design using ProteinMPNN (2022, methodology): “We started with a set of previously described protein backbones for two-component tetrahedral designs generated using a compute- and effort-intensive procedure that involved Rosetta sequence design followed by more than a week of manual intervention to eliminate unwanted substitutions (15).”
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).”
Energy-based models for atomic-resolution protein conformations (2020, background): “…from data, which, in combination with physically motivated force Published as a conference paper at ICLR 2020 ﬁelds, have contributed to the feasibility of de novo design of protein structures and functions (Kuhlman et al., 2003; Ambroggio & Kuhlman, 2006; Jiang et al., 2008; King et al., 2014).”
Web‐accessible molecular modeling with Rosetta: The Rosetta Online Server that Includes Everyone (ROSIE) (2018, background): “…resonance 9,10 and electron density information 11,12 in structure prediction and refinement, to the design of novel protein folds, 13,14 protein–protein interactions, 15,16 protein– small molecule interactions, 17,18 enzymes, 19,20 macro-molecular cages, 21,22 and protein–interacting peptides.”
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.”
Recent advances in de novo protein design: Principles, methods, and applications (2021, methodology): “Self-assembled nanocages with higher-order symmetries were designed by symmetric docking followed by Monte Carlo interface sequence design (140, 141).”
The coming of age of de novo protein design (2016, background): “78 and J. Fallas and G. Ueda, personal communication), tetrahedra 79,80 , octahedra 79 and open two-dimensional assemblies 81 (Fig.”
Towards atomic and close-to-atomic scale manufacturing (2019, background): “Although ACSM is still in its infancy, it shows significant potential for applications in many fields, such as drug development, efficient solar photovatic cells, efficient high power density fuel cells, single-molecule and single-electron sensors, biomedical sensors, high density computer memory, h”
Design of a hyperstable 60-subunit protein icosahedron (2016, unknown): “…coupled with computational protein-protein interface design has accurately generated protein assemblies with tetrahedral and octahedral symmetry 18,19 , but these relatively small ( 16 nm diameter) nanocages have limited use for packaging or delivery applications as they have little internal…”