ArticleProceedings of the National Academy of Sciences of the United States of America2024
Addressing epistasis in the design of protein function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Translating functional molecular knowledge into crop-breeding success.Nature reviews. Genetics · 2026Review
- Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function.Science advances · 2026Article
- Deciphering the evolutionary origin of the enantioselectivity of short-chain dehydrogenases from plants toward 1-borneol.Nature communications · 2026Article
- Collective Variable-Guided Engineering of the Free-Energy Surface of a Small Peptide.Journal of chemical information and modeling · 2026Article
- Machine-learning prediction of affinity and epistasis in the bovine pancreatic trypsin inhibitor-chymotrypsin complex.Protein science : a publication of the Protein Society · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Rigidifying Flexible Regions of a Bacterial Laccase Enables High-Temperature Aflatoxin B1 Degradation.Microorganisms · 2026Article
- Deep learning-guided dual-fitness evolution of T7 RNA polymerase for enhanced stability and activity.Nucleic acids research · 2026Article
- Selective control of ligand binding through a distal mutation that alters the protein native ensemble.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- 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
- The CspC:CspA heterodimer transduces germinant and co-germinant signals during Clostridioides difficile spore germination.PLoS biology · 2026Article
- Factors controlling protein evolvability-at the molecular scale.European biophysics journal : EBJ · 2026Article
- A Structural Landscape Depiction of Dynamic Stability Centers of Local Structure in Protein Thermostability Engineering.Research (Washington, D.C.) · 2026Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
- Computationally Designed Peroxygenases That Exhibit Diverse and Selective Terpene Oxyfunctionalization.ACS catalysis · 2025Article
- A Cyanobacterial Screening Platform for Rubisco Mutant Variants.ACS synthetic biology · 2025Article
- Encoding and decoding selectivity and promiscuity in the human chemokine-GPCR interaction network.Cell · 2025Article
- Importance of higher-order epistasis in protein sequence-function relationships.bioRxiv : the preprint server for biology · 2025Article
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2 authors.
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Abstract
Mutations in protein active sites can dramatically improve function. The active site, however, is densely packed and extremely sensitive to mutations. Therefore, some mutations may only be tolerated in combination with others in a phenomenon known as epistasis. Epistasis reduces the likelihood of obtaining improved functional variants and dramatically slows natural and lab evolutionary processes. Research has shed light on the molecular origins of epistasis and its role in shaping evolutionary trajectories and outcomes. In addition, sequence- and AI-based strategies that infer epistatic relationships from mutational patterns in natural or experimental evolution data have been used to design functional protein variants. In recent years, combinations of such approaches and atomistic design calculations have successfully predicted highly functional combinatorial mutations in active sites. These were used to design thousands of functional active-site variants, demonstrating that, while our understanding of epistasis remains incomplete, some of the determinants that are critical for accurate design are now sufficiently understood. We conclude that the space of active-site variants that has been explored by evolution may be expanded dramatically to enhance natural activities or discover new ones. Furthermore, design opens the way to systematically exploring sequence and structure space and mutational impacts on function, deepening our understanding and control over protein activity.
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