Computational design of soluble and functional membrane protein analogues.

Journal: Nature
PMID: 38898281

Abstract

De novo design of complex protein folds using solely computational means remains a substantial challenge. Here we use a robust deep learning pipeline to design complex folds and soluble analogues of integral membrane proteins. Unique membrane topologies, such as those from G-protein-coupled receptors, are not found in the soluble proteome, and we demonstrate that their structural features can be recapitulated in solution. Biophysical analyses demonstrate the high thermal stability of the designs, and experimental structures show remarkable design accuracy. The soluble analogues were functionalized with native structural motifs, as a proof of concept for bringing membrane protein functions to the soluble proteome, potentially enabling new approaches in drug discovery. In summary, we have designed complex protein topologies and enriched them with functionalities from membrane proteins, with high experimental success rates, leading to a de facto expansion of the functional soluble fold space.

Authors

  • Casper A Goverde
    Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Martin Pačesa
    Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland. m.pacesa@bioc.uzh.ch.
  • Nicolas Goldbach
    Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Lars J Dornfeld
    Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Petra E M Balbi
    Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Sandrine Georgeon
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Stéphane Rosset
    Laboratory of Protein Design and Immunoengineering, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Srajan Kapoor
    Department of Structural Biology, University at Buffalo, Buffalo, NY, USA.
  • Jagrity Choudhury
    Department of Structural Biology, University at Buffalo, Buffalo, NY, USA.
  • Justas Dauparas
    Department of Biochemistry and Institute for Protein Design, University of Washington, Washington, WA, USA.
  • Christian Schellhaas
    Laboratory of Protein Design and Immunoengineering, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Simon Kozlov
    Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • David Baker
    Department of Biochemistry, University of Washington, Seattle, Washington.
  • Sergey Ovchinnikov
    Center for Systems Biology, Harvard University, Cambridge, MA 02138, United States.
  • Alex J Vecchio
    Department of Structural Biology, University at Buffalo, Buffalo, NY, USA.
  • Bruno E Correia
    Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

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