ArticleMolecular biology and evolution2016
Optimization of Conformational Dynamics in an Epistatic Evolutionary Trajectory.
Article in Molecular biology and evolution, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- 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
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Active site loops of membrane-anchored metallo-β-lactamases from environmental bacteria determine cephalosporinase activity.Antimicrobial agents and chemotherapy · 2025Article
- The emerging concern of IMP variants being resistant to the only IMP-type metallo-β-lactamase inhibitor, xeruborbactam.Antimicrobial agents and chemotherapy · 2025Article
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.Nature catalysis · 2024Article
- Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution.Nature communications · 2023Article
- Gating interactions steer loop conformational changes in the active site of the L1 metallo-β-lactamase.eLife · 2023Article
- Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.Molecular biology and evolution · 2022Article
- Bypassing evolutionary dead ends and switching the rate-limiting step of a human immunotherapeutic enzyme.Nature catalysis · 2022Article
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- Different Conformations Revealed by NMR Underlie Resistance to Ceftazidime/Avibactam and Susceptibility to Meropenem and Imipenem among D179Y Variants of KPC β-Lactamase.Antimicrobial agents and chemotherapy · 2022Article
- Localising individual atoms of tryptophan side chains in the metallo-Magnetic resonance (Gottingen, Germany) · 2022Article
- Second-Shell Amino Acid R266 Helps DetermineBiochemistry · 2021Article
- Reviewing Challenges of Predicting Protein Melting Temperature Change Upon Mutation Through the Full Analysis of a Highly Detailed Dataset with High-Resolution Structures.Molecular biotechnology · 2021Review
- Two β-Lactamase Variants with Reduced Clavulanic Acid Inhibition Display Different Millisecond Dynamics.Antimicrobial agents and chemotherapy · 2021Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Evolutionary Trajectory of the Tet(X) Family: Critical Residue Changes towards High-Level Tigecycline Resistance.mSystems · 2021Article
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4 authors.
Funding
Abstract
The understanding of protein evolution depends on the ability to relate the impact of mutations on molecular traits to organismal fitness. Biological activity and robustness have been regarded as important features in shaping protein evolutionary landscapes. Conformational dynamics, which is essential for protein function, has received little attention in the context of evolutionary analyses. Here we employ NMR spectroscopy, the chief experimental tool to describe protein dynamics at atomic level in solution at room temperature, to study the intrinsic dynamic features of a metallo- Β: -lactamase enzyme and three variants identified during a directed evolution experiment that led to an expanded substrate profile. We show that conformational dynamics in the catalytically relevant microsecond to millisecond timescale is optimized along the favored evolutionary trajectory. In addition, we observe that the effects of mutations on dynamics are epistatic. Mutation Gly262Ser introduces slow dynamics on several residues that surround the active site when introduced in the wild-type enzyme. Mutation Asn70Ser removes the slow dynamics observed for few residues of the wild-type enzyme, but increases the number of residues that undergo slow dynamics when introduced in the Gly262Ser mutant. These effects on dynamics correlate with the epistatic interaction between these two mutations on the bacterial phenotype. These findings indicate that conformational dynamics is an evolvable trait, and that proteins endowed with more dynamic active sites also display a larger potential for promoting evolution.
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