ArticleMolecular biology and evolution2019
High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection.
Article in Molecular biology and evolution, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 82 citations in OpenAlex.
- Quantifying protein unfolding kinetics with a high-throughput microfluidic platform.Cell systems · 2026Article
- Evolutionary Convergence on a Dihydrofolate Reductase Mutation Drives Trimethoprim-Sulfamethoxazole Resistance in Burkholderia thailandensis.ACS infectious diseases · 2026Article
- Conserved protein sequence-structure signatures identify antibiotic resistance genes from the human microbiome.Microbiome · 2026Article
- Chaperonin recognition of protein dynamics drives drug resistance.bioRxiv : the preprint server for biology · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- Continuous targeted hypermutation with a tunable mutation window.Nature communications · 2025Article
- Clinical and bacterial determinants of unfavorable tuberculosis treatment outcomes: an observational study in Georgia.Genome medicine · 2025Observational
- From Binding to Catalysis: Emergence of a Rudimentary Enzyme Conferring Intrinsic Antibiotic Resistance.Molecular biology and evolution · 2025Article
- Exploring antibiotic resistance in diverse homologs of the dihydrofolate reductase protein family through broad mutational scanning.Science advances · 2025Article
- Higher-order epistasis drives evolutionary unpredictability toward novel antibiotic resistance.bioRxiv : the preprint server for biology · 2025Article
- A Thermodynamic Cycle to Predict the Competitive Inhibition Outcomes of an Evolving Enzyme.Journal of chemical theory and computation · 2025Article
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- A Short-Term View of Protein Sequence Evolution from Salmonella.Genome biology and evolution · 2025Article
- A thermodynamic cycle to predict the competitive inhibition outcomes of an evolving enzyme.bioRxiv : the preprint server for biology · 2025Article
- 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
- High throughput mutational scanning of a protein via alchemistry on a high-performance computing resource.bioRxiv : the preprint server for biology · 2024Article
- [Applications of native mass spectrometry and ultraviolet photodissociation in protein structure and interaction analysis].Se pu = Chinese journal of chromatography · 2024Review
- Genotype sampling for deep-learning assisted experimental mapping of a combinatorially complete fitness landscape.Bioinformatics (Oxford, England) · 2024Article
- Robust genetic codes enhance protein evolvability.PLoS biology · 2024Article
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
Evolutionary fitness landscapes of several antibiotic target proteins have been comprehensively mapped showing strong high-order epistasis between mutations, but understanding these effects at the biochemical and structural levels remained open. Here, we carried out an extensive experimental and computational study to quantitatively understand the evolutionary dynamics of Escherichia coli dihydrofolate reductase (DHFR) enzyme in the presence of trimethoprim-induced selection. To facilitate this, we developed a new in vitro assay for rapidly characterizing DHFR steady-state kinetics. Biochemical and structural characterization of resistance-conferring mutations targeting a total of ten residues spanning the substrate binding pocket of DHFR revealed distinct changes in the catalytic efficiencies of mutated DHFR enzymes. Next, we measured biochemical parameters (Km, Ki, and kcat) for a mutant library carrying all possible combinations of six resistance-conferring DHFR mutations and quantified epistatic interactions between them. We found that the high-order epistasis in catalytic power of DHFR (kcat and Km) creates a rugged fitness landscape under trimethoprim selection. Taken together, our data provide a concrete illustration of how epistatic coupling at the level of biochemical parameters can give rise to complex fitness landscapes, and suggest new strategies for developing mutant specific inhibitors.
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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.