De novo design of protein interactions with learned surface fingerprints.

Journal: Nature
Published Date: Apr 26, 2023

Abstract

Physical interactions between proteins are essential for most biological processes governing life. However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications. Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions. We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function.

Authors

  • Pablo Gainza
    Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Sarah Wehrle
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Alexandra Van Hall-Beauvais
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Anthony Marchand
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Andreas Scheck
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Zander Harteveld
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Stephen Buckley
    Cancer Research at UCC, University College Cork, Cork, Ireland.
  • Dongchun Ni
    Laboratory of Biological Electron Microscopy, Institute of Physics, School of Basic Science, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Shuguang Tan
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • Freyr Sverrisson
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Casper Goverde
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Priscilla Turelli
    Laboratory of Virology and Genetics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Charlène Raclot
    Laboratory of Virology and Genetics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Alexandra Teslenko
    Laboratory of Biophysical Chemistry of Macromolecules, School of Basic Sciences, Institute of Chemical Sciences and Engineering (ISIC), École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Martin Pačesa
    Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland. m.pacesa@bioc.uzh.ch.
  • Stéphane Rosset
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Sandrine Georgeon
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Jane Marsden
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Aaron Petruzzella
    Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Kefang Liu
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • Zepeng Xu
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • Yan Chai
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • Pu Han
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • George F Gao
    CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • Elisa Oricchio
    Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Beat Fierz
    Laboratory of Biophysical Chemistry of Macromolecules, School of Basic Sciences, Institute of Chemical Sciences and Engineering (ISIC), École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Didier Trono
    Laboratory of Virology and Genetics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Henning Stahlberg
    Laboratory of Biological Electron Microscopy, Institute of Physics, School of Basic Science, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Michael Bronstein
    Department of Computing, Faculty of Engineering, Imperial College London, London, SW7 2AZ, UK.
  • Bruno E Correia
    Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

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