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De novo design of protein interactions with learned surface fingerprints.

ABSTRACT: Physical interactions between proteins are essential for most biological processes governing life¹. 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^2-9. 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 interactions¹⁰. 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.

SUBMITTER: Gainza P

PROVIDER: S-EPMC10131520 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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De novo design of protein interactions with learned surface fingerprints.

Gainza Pablo P Wehrle Sarah S Van Hall-Beauvais Alexandra A Marchand Anthony A Scheck Andreas A Harteveld Zander Z Buckley Stephen S Ni Dongchun D Tan Shuguang S Sverrisson Freyr F Goverde Casper C Turelli Priscilla P Raclot Charlène C Teslenko Alexandra A Pacesa Martin M Rosset Stéphane S Georgeon Sandrine S Marsden Jane J Petruzzella Aaron A Liu Kefang K Xu Zepeng Z Chai Yan Y Han Pu P Gao George F GF Oricchio Elisa E Fierz Beat B Trono Didier D Stahlberg Henning H Bronstein Michael M Correia Bruno E BE

Nature 20230426 7959

Physical interactions between proteins are essential for most biological processes governing life<sup>1</sup>. 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 appli ...[more]

PMID: 37100904

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Project description:Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

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De novo design of protein interactions with learned surface fingerprints.

Publications

De novo design of protein interactions with learned surface fingerprints.

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