A generic framework for hierarchical de novo protein design
Open accessPublished version of a preprint
Abstract
De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test for our understanding of the underlying physical principles of protein folding and may lead to the development of proteins with unmatched functional characteristics. The first fundamental challenge of de novo design is to devise “designable” structural templates leading to sequences that will adopt the predicted fold. Here, we built on the TopoBuilder (TB) de novo design method, to automatically assemble structural templates with native-like features starting from string descriptors that capture the overall topology of proteins. Our framework eliminates the dependency of hand-crafted and fold-specific rules through an iterative, data-driven approach that extracts geometrical parameters from structural tertiary motifs. We evaluated the TopoBuilder framework by designing sequences for a set of five protein folds and experimental characterization revealed that several sequences were folded and stable in solution. The TopoBuilder de novo design framework will be broadly useful to guide the generation of artificial proteins with customized geometries, enabling the exploration of the protein universe.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
The coming of age of de novo protein design
Huang, P.-S., Boyken, S. E., & Baker, D. (2016) · Nature · doi:10.1038/nature19946 · Cited by 1,478 · see citing works
Proof of principle for epitope-focused vaccine design
Correia, B. E., Bates, J. T., Loomis, R. J., Baneyx, G., Carrico, C., Jardine, J. G., Rupert, P., Correnti, C., Kalyuzhniy, O., Vittal, V., et al. (2014) · Nature · doi:10.1038/nature12966 · Cited by 555 · see citing works
Self-citationMassively parallel de novo protein design for targeted therapeutics
Chevalier, A., Silva, D.-A., Rocklin, G. J., Hicks, D. R., Vergara, R., Murapa, P., Bernard, S. M., Zhang, L., Lam, K.-H., Yao, G., et al. (2017) · Nature · doi:10.1038/nature23912 · Cited by 453 · cited 2× · see citing works
“Many de novo design approaches are likely to fail due to the lack of designability of the starting structural templates, requiring multiple iterative rounds of human-guided and experimental optimizations [4], [5].”
BackgroundComputational design of water-soluble α-helical barrels
Thomson, A. R., Wood, C. W., Burton, A. J., Bartlett, G. J., Sessions, R. B., Brady, R. L., & Woolfson, D. N. (2014) · Science · doi:10.1126/science.1257452 · Cited by 330 · see citing works
High thermodynamic stability of parametrically designed helical bundles
Huang, P.-S., Oberdorfer, G., Xu, C., Pei, X. Y., Nannenga, B. L., Rogers, J. M., DiMaio, F., Gonen, T., Luisi, B., & Baker, D. (2014) · Science · doi:10.1126/science.1257481 · Cited by 277 · see citing works
De novo protein design enables the precise induction of RSV-neutralizing antibodies
Sesterhenn, F., Yang, C., Bonet, J., Cramer, J. T., Wen, X., Wang, Y., Chiang, C.-I., Abriata, L. A., Kucharska, I., Castoro, G., et al. (2020) · Science · doi:10.1126/science.aay5051 · Cited by 191 · see citing works
Self-citationBottom-up de novo design of functional proteins with complex structural features
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- Authors
- Harteveld, Z., Bonet, J., Rosset, S., Yang, C., Sesterhenn, F., & Correia, B. E.
- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Correia, Bruno E.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2022-10-17
- Volume
- 119
- Issue
- 43
- Pages
- e2206111119-e2206111119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9618129
- OpenAlex
- W4306641699
- Cited by
- 21
- References
- 8
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 3
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- Biltema Foundation
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centro Svizzero di Calcolo Scientifico
- National Supercomputing Centre Singapore
- H2020 European Research Council (716058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- de novo protein design, structural templates, protein topology, geometric parameters, protein folding, artificial proteins, protein stability
- MeSH terms
- Models, Molecular, Proteins, Protein Engineering, Protein Folding
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