ArticleCell systems2025
Evolutionary paths that link orthogonal pairs of binding proteins.
Article in Cell systems, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Structural ontogeny of protein-protein interactions.Science (New York, N.Y.) · 2026Article
- Inference and Visualization of Complex Genotype-Phenotype Maps.Molecular biology and evolution · 2026Article
- Graph attention with structural features improves the generalizability of identifying functional sequences at a protein interface.bioRxiv : the preprint server for biology · 2025Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Abstract
Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if they exhibit sufficient affinity. Until now, finding a fully functional single-mutation path connecting orthogonal pairs could only be achieved by full enumeration of intermediates and was restricted to pairs that were mutationally close. We present a computational framework for discovering single-mutation paths with low molecular strain and apply it to two orthogonal bacterial endonuclease-immunity pairs separated by 17 interfacial mutations. By including mutations that bridge identities that could not be exchanged by single-nucleotide mutations, we discovered a strain-free 19-mutation path that was fully functional in vivo. The change in binding preference occurred remarkably abruptly, resulting from only one radical mutation in each partner. Furthermore, each of the specificity-switch mutations increased fitness, demonstrating that functional divergence could be driven by positive Darwinian selection.
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