ArticleNature communications2021
Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 119 citations in OpenAlex.
- Advances in amidases and urethanases as depolymerization biocatalysts.Nature chemical biology · 2026Review
- Rank-guided learning accelerates automated enzyme engineering.Nature communications · 2026Article
- 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
- Creating highly active fluoroacetate dehalogenases via gate-based synergetic chain design.Nature communications · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- Microfluidic-Assisted Evolution of a Robust NADChemSusChem · 2025Article
- Article
- Machine learning-guided evolution of pyrrolysyl-tRNA synthetase for improved incorporation efficiency of diverse noncanonical amino acids.Nature communications · 2025Article
- Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape.Science (New York, N.Y.) · 2025Article
- Ultrahigh-Throughput Activity Engineering of Promiscuous Amidases through a Fluorescence-Activated Cell Sorting Assay.ACS catalysis · 2025Article
- Rate-Engineered Plasmon-Enhanced Fluorescence for Real-Time Microsecond Dynamics of Single Biomolecules.Nano letters · 2024Article
- Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants.ACS catalysis · 2024Review
- Opportunities and Challenges for Machine Learning-Assisted Enzyme Engineering.ACS central science · 2024Review
- Computational redesign of taxane-10β-hydroxylase for de novo biosynthesis of a key paclitaxel intermediate.Applied microbiology and biotechnology · 2023Article
- Machine Learning-Guided Protein Engineering.ACS catalysis · 2023Review
- Fishing for Catalysis: Experimental Approaches to Narrowing Search Space in Directed Evolution of Enzymes.JACS Au · 2023Review
- Accurate Prediction of Enzyme Thermostabilization with Rosetta Using AlphaFold Ensembles.Journal of chemical information and modeling · 2023Article
- Tuning Selectivity in CalA Lipase: Beyond Tunnel Engineering.Biochemistry · 2023Article
- How can we discover developable antibody-based biotherapeutics?Frontiers in molecular biosciences · 2023Review
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 7 countries.
Funding
Abstract
Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s.
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Registered trials
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.