pocketz.doi.bio/2026-05-02_070026_nature_s41586-026-10328-7
The past, present and future of de novo protein design | Nature
URL: https://www.nature.com/articles/s41586-026-10328-7
Saved: 2026-05-02T14:00:26.754Z
Review Published: 29 April 2026 The past, present and future of de novo protein design Wei Yang, Shunzhi Wang, Gyu Rie Lee, Jason Z. Zhang, Alexis Courbet, David Juergens, Xinru Wang, Thomas Schlichthaerle, Mohamad Abedi, Robert Ragotte, Linna An, Indrek Kalvet, Sam Pellock, Ljubica Mihaljevic, Cameron Glasscock, Arvind Pillai, Adam Broerman, Nathan Ennist, Ella Haefner, Nora McNamara-Bordewick, Ian Haydon, Lance Stewart, Gaurav Bhardwaj & David Baker
Nature volume 652, pages 1139–1152 (2026)Cite this article
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Abstract
With deep-learning-powered advances in protein design methods, there is an ongoing paradigm shift in protein engineering from random selection to intentional computational design methods. Here we describe the current state of de novo protein design. While there is still room for improvement in success rates and activities, the long-standing challenges of designing new protein structures, assemblies and protein binders are close to being solved. The key current questions in these areas are not how to design, but what to design, and open-source design methodology such as RFdiffusion and ProteinMPNN together with protein structure prediction tools enable biochemists and molecular biologists to broadly explore possible applications. There has also been considerable progress in the de novo design of small-molecule target binders, enzymes and multistate protein systems. Current challenges for methods development include design of catalysts for reactions with high energy barriers and, more generally, design of switches and nanomachines that integrate binding, conformational change and catalysis. Over the next five to ten years, we anticipate the design of sophisticated protein nanomachines and materials with functionality ranging far beyond that generated during natural evolution for a wide range of applications in medicine, technology and sustainability.
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Acknowledgements
We thank our colleagues in the Baker Lab, the Institute for Protein Design and the Rosetta community for their contributions to much of the work described in this Review.
Author information Author notes
These authors contributed equally: Wei Yang, Shunzhi Wang, Gyu Rie Lee, Jason Z. Zhang
Authors and Affiliations
Department of Biochemistry, University of Washington, Seattle, WA, USA
Wei Yang, Shunzhi Wang, Gyu Rie Lee, Jason Z. Zhang, Alexis Courbet, David Juergens, Xinru Wang, Thomas Schlichthaerle, Mohamad Abedi, Robert Ragotte, Linna An, Indrek Kalvet, Sam Pellock, Ljubica Mihaljevic, Cameron Glasscock, Arvind Pillai, Adam Broerman, Nathan Ennist, Ella Haefner, Nora McNamara-Bordewick, Ian Haydon, Lance Stewart & David Baker
Institute for Protein Design, University of Washington, Seattle, WA, USA
Wei Yang, Shunzhi Wang, Gyu Rie Lee, Jason Z. Zhang, Alexis Courbet, David Juergens, Xinru Wang, Thomas Schlichthaerle, Mohamad Abedi, Robert Ragotte, Linna An, Indrek Kalvet, Sam Pellock, Ljubica Mihaljevic, Cameron Glasscock, Arvind Pillai, Adam Broerman, Nathan Ennist, Ella Haefner, Nora McNamara-Bordewick, Ian Haydon, Lance Stewart, Gaurav Bhardwaj & David Baker
Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation (SMART), Shenzhen, China
Wei Yang
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
Shunzhi Wang, Gyu Rie Lee, Jason Z. Zhang, Alexis Courbet, Mohamad Abedi, Indrek Kalvet & David Baker
Institute for Systems Genetics, NYU Langone Health, New York, NY, USA
Shunzhi Wang
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
Gyu Rie Lee
Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA
Jason Z. Zhang & Mohamad Abedi
Center for Drug Discovery, Northeastern University, Boston, MA, USA
Xinru Wang
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
Xinru Wang
TUM School of Natural Sciences, Technical University of Munich, Munich, Germany
Thomas Schlichthaerle
Department of BioSciences, Rice University, Houston, TX, USA
Cameron Glasscock
Department of Structural and Molecular Biochemistry, North Carolina State University, Raleigh, NC, USA
Nathan Ennist
Department of Physics, North Carolina State University, Raleigh, NC, USA
Nathan Ennist
Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
Gaurav Bhardwaj
Contributions
The different sections were contributed by different author groups. D.B., D.J., G.B. and W.Y. contributed to the section on protein design methodology. D.B., A.C., S.W. and W.Y. contributed to the section on protein folds and assembly. D.B., J.Z.Z., X.W., T.S., M.A., R.R. and W.Y. contributed to the section on the design of binding to protein targets. D.B., G.R.L., L.A., I.K., S.P. and L.M. contributed to the section on small-molecule binders, sensors and enzymes. D.B., L.S., C.G., A.P., A.B., N.E. and W.Y. contributed to the Outlook section. E.H. and N.M.-B. contributed to Supplementary Table 1. S.W. contributed to Box 1. W.Y., G.R.L., J.Z.Z., S.W. and I.H. contributed to the illustration design and rendering. All of the authors reviewed the manuscript and provided feedback and revisions to their respective sections.
Corresponding author
Correspondence to David Baker.
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Yang, W., Wang, S., Lee, G.R. et al. The past, present and future of de novo protein design. Nature 652, 1139–1152 (2026). https://doi.org/10.1038/s41586-026-10328-7
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Received 16 September 2024
Accepted 20 February 2026
Published 29 April 2026
Version of record 29 April 2026
Issue date 30 April 2026
DOI https://doi.org/10.1038/s41586-026-10328-7
Subjects Biomaterials – proteins Protein design Proteins