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Accurate de novo design of hyperstable constrained peptides

Author

Listed:
  • Gaurav Bhardwaj

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Vikram Khipple Mulligan

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Christopher D. Bahl

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Jason M. Gilmore

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Peta J. Harvey

    (Institute for Molecular Bioscience, The University of Queensland)

  • Olivier Cheneval

    (Institute for Molecular Bioscience, The University of Queensland)

  • Garry W. Buchko

    (Seattle Structural Genomics Center for Infectious Diseases, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory)

  • Surya V. S. R. K. Pulavarti

    (State University of New York at Buffalo)

  • Quentin Kaas

    (Institute for Molecular Bioscience, The University of Queensland)

  • Alexander Eletsky

    (State University of New York at Buffalo)

  • Po-Ssu Huang

    (University of Washington
    Institute for Protein Design, University of Washington)

  • William A. Johnsen

    (Fred Hutchinson Cancer Research Center)

  • Per Jr Greisen

    (University of Washington
    Institute for Protein Design, University of Washington
    Global Research, Novo Nordisk A/S)

  • Gabriel J. Rocklin

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Yifan Song

    (University of Washington
    Institute for Protein Design, University of Washington
    Cyrus Biotechnology)

  • Thomas W. Linsky

    (University of Washington
    Institute for Protein Design, University of Washington)

  • Andrew Watkins

    (New York University)

  • Stephen A. Rettie

    (Institute for Protein Design, University of Washington)

  • Xianzhong Xu

    (State University of New York at Buffalo)

  • Lauren P. Carter

    (Institute for Protein Design, University of Washington)

  • Richard Bonneau

    (New York University
    Center for Computational Biology, Simons Foundation)

  • James M. Olson

    (Fred Hutchinson Cancer Research Center)

  • Evangelos Coutsias

    (Applied Mathematics and Statistics and Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook)

  • Colin E. Correnti

    (Fred Hutchinson Cancer Research Center)

  • Thomas Szyperski

    (State University of New York at Buffalo)

  • David J. Craik

    (Institute for Molecular Bioscience, The University of Queensland)

  • David Baker

    (University of Washington
    Institute for Protein Design, University of Washington
    Howard Hughes Medical Institute, University of Washington)

Abstract

Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets. Here we describe the development of computational methods for accurate de novo design of conformationally restricted peptides, and the use of these methods to design 18–47 residue, disulfide-crosslinked peptides, a subset of which are heterochiral and/or N–C backbone-cyclized. Both genetically encodable and non-canonical peptides are exceptionally stable to thermal and chemical denaturation, and 12 experimentally determined X-ray and NMR structures are nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs.

Suggested Citation

  • Gaurav Bhardwaj & Vikram Khipple Mulligan & Christopher D. Bahl & Jason M. Gilmore & Peta J. Harvey & Olivier Cheneval & Garry W. Buchko & Surya V. S. R. K. Pulavarti & Quentin Kaas & Alexander Eletsk, 2016. "Accurate de novo design of hyperstable constrained peptides," Nature, Nature, vol. 538(7625), pages 329-335, October.
  • Handle: RePEc:nat:nature:v:538:y:2016:i:7625:d:10.1038_nature19791
    DOI: 10.1038/nature19791
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    Cited by:

    1. Edin Muratspahić & Kristine Deibler & Jianming Han & Nataša Tomašević & Kirtikumar B. Jadhav & Aina-Leonor Olivé-Marti & Nadine Hochrainer & Roland Hellinger & Johannes Koehbach & Jonathan F. Fay & Mo, 2023. "Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Julia Koehler Leman & Sergey Lyskov & Steven M. Lewis & Jared Adolf-Bryfogle & Rebecca F. Alford & Kyle Barlow & Ziv Ben-Aharon & Daniel Farrell & Jason Fell & William A. Hansen & Ameya Harmalkar & Je, 2021. "Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Zengping Duan & Chuilian Kong & Shihui Fan & Chuanliu Wu, 2024. "Triscysteine disulfide-directing motifs enabling design and discovery of multicyclic peptide binders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. SM Bargeen Alam Turzo & Justin T. Seffernick & Amber D. Rolland & Micah T. Donor & Sten Heinze & James S. Prell & Vicki H. Wysocki & Steffen Lindert, 2022. "Protein shape sampled by ion mobility mass spectrometry consistently improves protein structure prediction," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Karen J. Gonzalez & Jiachen Huang & Miria F. Criado & Avik Banerjee & Stephen M. Tompkins & Jarrod J. Mousa & Eva-Maria Strauch, 2024. "A general computational design strategy for stabilizing viral class I fusion proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Sicong Yao & Adam Moyer & Yiwu Zheng & Yang Shen & Xiaoting Meng & Chong Yuan & Yibing Zhao & Hongwei Yao & David Baker & Chuanliu Wu, 2022. "De novo design and directed folding of disulfide-bridged peptide heterodimers," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Tamuka M. Chidyausiku & Soraia R. Mendes & Jason C. Klima & Marta Nadal & Ulrich Eckhard & Jorge Roel-Touris & Scott Houliston & Tibisay Guevara & Hugh K. Haddox & Adam Moyer & Cheryl H. Arrowsmith & , 2022. "De novo design of immunoglobulin-like domains," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Jorge Roel-Touris & Marta Nadal & Enrique Marcos, 2023. "Single-chain dimers from de novo immunoglobulins as robust scaffolds for multiple binding loops," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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