Computational design of soluble and functional membrane protein analogues

Casper A. Goverde, Martin Pacesa, Nicolas Goldbach, Lars J. Dornfeld, Petra E. M. Balbi, Sandrine Georgeon, Stéphane Rosset, Srajan Kapoor, Jagrity Choudhury, Justas Dauparas, Christian Schellhaas, Simon Kozlov, David Baker, Sergey Ovchinnikov, Alex J. Vecchio and Bruno E. Correia ()
Additional contact information
Casper A. Goverde: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Martin Pacesa: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Nicolas Goldbach: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Lars J. Dornfeld: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Petra E. M. Balbi: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Sandrine Georgeon: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Stéphane Rosset: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Srajan Kapoor: University at Buffalo
Jagrity Choudhury: University at Buffalo
Justas Dauparas: University of Washington
Christian Schellhaas: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics
Simon Kozlov: Massachusetts Institute of Technology
David Baker: University of Washington
Sergey Ovchinnikov: Massachusetts Institute of Technology
Alex J. Vecchio: University at Buffalo
Bruno E. Correia: École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics

Nature, 2024, vol. 631, issue 8020, 449-458

Abstract: Abstract De novo design of complex protein folds using solely computational means remains a substantial challenge1. 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 receptors2, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07601-y

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