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De novo design of high-affinity protein binders to bioactive helical peptides

View ORCID ProfileSusana Vázquez Torres, View ORCID ProfilePhilip J. Y. Leung, Isaac D. Lutz, View ORCID ProfilePreetham Venkatesh, View ORCID ProfileJoseph L. Watson, Fabian Hink, View ORCID ProfileHuu-Hien Huynh, View ORCID ProfileAndy Hsien-Wei Yeh, View ORCID ProfileDavid Juergens, View ORCID ProfileNathaniel R. Bennett, View ORCID ProfileAndrew N. Hoofnagle, Eric Huang, View ORCID ProfileMichael J MacCoss, Marc Expòsit, View ORCID ProfileGyu Rie Lee, View ORCID ProfilePaul M. Levine, View ORCID ProfileXinting Li, Mila Lamb, View ORCID ProfileElif Nihal Korkmaz, View ORCID ProfileJeff Nivala, Lance Stewart, View ORCID ProfileJoseph M. Rogers, View ORCID ProfileDavid Baker
doi: https://doi.org/10.1101/2022.12.10.519862
Susana Vázquez Torres
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
3Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA 98105, USA
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Philip J. Y. Leung
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
4Graduate Program in Molecular Engineering, University of Washington, Seattle, WA 98105, USA
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Isaac D. Lutz
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
5Department of Bioengineering, University of Washington, Seattle, WA, USA
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Preetham Venkatesh
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
3Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, WA 98105, USA
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Joseph L. Watson
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Fabian Hink
6Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
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Huu-Hien Huynh
7Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98105, USA
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Andy Hsien-Wei Yeh
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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David Juergens
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
4Graduate Program in Molecular Engineering, University of Washington, Seattle, WA 98105, USA
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Nathaniel R. Bennett
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
4Graduate Program in Molecular Engineering, University of Washington, Seattle, WA 98105, USA
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Andrew N. Hoofnagle
7Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98105, USA
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Eric Huang
8Department of Genome Sciences, University of Washington, Seattle, WA 98195
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Michael J MacCoss
8Department of Genome Sciences, University of Washington, Seattle, WA 98195
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Marc Expòsit
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
4Graduate Program in Molecular Engineering, University of Washington, Seattle, WA 98105, USA
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Gyu Rie Lee
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Paul M. Levine
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Xinting Li
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Mila Lamb
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Elif Nihal Korkmaz
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Jeff Nivala
10School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
11Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA, USA
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Lance Stewart
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
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Joseph M. Rogers
6Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark
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  • For correspondence: dabaker@uw.edu
David Baker
1Department of Biochemistry, University of Washington, Seattle, WA, USA
2Institute for Protein Design, University of Washington, Seattle, WA, USA
9Howard Hughes Medical Institute, University of Washington, Seattle, WA 98105,USA
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  • ORCID record for David Baker
  • For correspondence: dabaker@uw.edu
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Abstract

Many peptide hormones form an alpha-helix upon binding their receptors1–4, and sensitive detection methods for them could contribute to better clinical management. De novo protein design can now generate binders with high affinity and specificity to structured proteins5,6. However, the design of interactions between proteins and short helical peptides is an unmet challenge. Here, we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that with the RFdiffusion generative model, picomolar affinity binders can be generated to helical peptide targets either by noising and then denoising lower affinity designs generated with other methods, or completely de novo starting from random noise distributions; to our knowledge these are the highest affinity designed binding proteins against any protein or small molecule target generated directly by computation without any experimental optimization. The RFdiffusion designs enable the enrichment of parathyroid hormone or other bioactive peptides in human plasma and subsequent detection by mass spectrometry, and bioluminescence-based protein biosensors. Capture reagents for bioactive helical peptides generated using the methods described here could aid in the improved diagnosis and therapeutic management of human diseases.7,8

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Increased figure resolution

  • https://www.bakerlab.org/wp-content/uploads/2022/11/diffusion_animation_PTHbinder.gif

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted December 15, 2022.
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De novo design of high-affinity protein binders to bioactive helical peptides
Susana Vázquez Torres, Philip J. Y. Leung, Isaac D. Lutz, Preetham Venkatesh, Joseph L. Watson, Fabian Hink, Huu-Hien Huynh, Andy Hsien-Wei Yeh, David Juergens, Nathaniel R. Bennett, Andrew N. Hoofnagle, Eric Huang, Michael J MacCoss, Marc Expòsit, Gyu Rie Lee, Paul M. Levine, Xinting Li, Mila Lamb, Elif Nihal Korkmaz, Jeff Nivala, Lance Stewart, Joseph M. Rogers, David Baker
bioRxiv 2022.12.10.519862; doi: https://doi.org/10.1101/2022.12.10.519862
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De novo design of high-affinity protein binders to bioactive helical peptides
Susana Vázquez Torres, Philip J. Y. Leung, Isaac D. Lutz, Preetham Venkatesh, Joseph L. Watson, Fabian Hink, Huu-Hien Huynh, Andy Hsien-Wei Yeh, David Juergens, Nathaniel R. Bennett, Andrew N. Hoofnagle, Eric Huang, Michael J MacCoss, Marc Expòsit, Gyu Rie Lee, Paul M. Levine, Xinting Li, Mila Lamb, Elif Nihal Korkmaz, Jeff Nivala, Lance Stewart, Joseph M. Rogers, David Baker
bioRxiv 2022.12.10.519862; doi: https://doi.org/10.1101/2022.12.10.519862

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