ArticleNature communications2023
Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Deciphering functional diversity and structural determinants of substrate specificity in fungal glycoside hydrolase family 5_5 cellulases.Applied and environmental microbiology · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational 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
- Investigation of salt-bridge interactions underlying salt activation of halophilic methionine sulfoxide reductase A.Frontiers in microbiology · 2026Article
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Co-evolution of alpha-helical transmembrane protein residues: large-scale variant profiling and complete mutational landscape of 2277 known PDB entries representing 504 unique human protein sequences.Journal of molecular evolution · 2025Article
- Article
- Efficient Searches in Protein Sequence Space Through AI-Driven Iterative Learning.International journal of molecular sciences · 2025Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.Nature communications · 2025Article
- Tailoring industrial enzymes for thermostability and activity evolution by the machine learning-based iCASE strategy.Nature communications · 2025Article
- Optimizing enzyme thermostability by combining multiple mutations using protein language model.mLife · 2024Article
- The origin of mutational epistasis.European biophysics journal : EBJ · 2024Article
- Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.Nature communications · 2024Article
- The simplicity of protein sequence-function relationships.Nature communications · 2024Article
- Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape.International journal of molecular sciences · 2024Article
- Network of epistatic interactions in an enzyme active site revealed by large-scale deep mutational scanning.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Enzyme evolution is characterized by constant alterations of the intramolecular residue networks supporting their functions. The rewiring of these network interactions can give rise to epistasis. As mutations accumulate, the epistasis observed across diverse genotypes may appear idiosyncratic, that is, exhibit unique effects in different genetic backgrounds. Here, we unveil a quantitative picture of the prevalence and patterns of epistasis in enzyme evolution by analyzing 41 fitness landscapes generated from seven enzymes. We show that >94% of all mutational and epistatic effects appear highly idiosyncratic, which greatly distorted the functional prediction of the evolved enzymes. By examining seemingly idiosyncratic changes in epistasis along adaptive trajectories, we expose several instances of higher-order, intramolecular rewiring. Using complementary structural data, we outline putative molecular mechanisms explaining higher-order epistasis along two enzyme trajectories. Our work emphasizes the prevalence of epistasis and provides an approach to exploring this phenomenon through a molecular lens.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.