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# 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

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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

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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

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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This file contains Supplementary Table 1 and Supplementary Fig. 1.

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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

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