De novo design of high-affinity binders of bioactive helical peptides.

Journal: Nature
PMID: 38109936

Abstract

Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease. De novo protein design can now generate binders with high affinity and specificity to structured proteins. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful.

Authors

  • Susana Vázquez Torres
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Philip J Y Leung
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Preetham Venkatesh
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Isaac D Lutz
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Fabian Hink
    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Huu-Hien Huynh
    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • Jessica Becker
    Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • Andy Hsien-Wei Yeh
    Department of Biochemistry, University of Washington, Seattle, WA, USA. hsyeh@ucsc.edu.
  • David Juergens
    Department of Biochemistry, University of Washington, Seattle, WA 98105.
  • Nathaniel R Bennett
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Andrew N Hoofnagle
    Department of Laboratory Medicine, University of Washington, Seattle, WA.
  • Eric Huang
    Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Michael J MacCoss
    Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Marc Expòsit
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Gyu Rie Lee
    Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
  • Asim K Bera
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Alex Kang
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Joshmyn De La Cruz
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Paul M Levine
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Xinting Li
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Mila Lamb
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Stacey R Gerben
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Analisa Murray
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Piper Heine
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Elif Nihal Korkmaz
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Jeff Nivala
    School of Computer Science and Engineering, University of Washington, Seattle, WA, USA.
  • Lance Stewart
    Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • Joseph L Watson
    Department of Biochemistry, University of Washington, Seattle, WA 98105, USA.
  • Joseph M Rogers
    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. joseph.rogers@sund.ku.dk.
  • David Baker
    Department of Biochemistry, University of Washington, Seattle, Washington.

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