ArticleInternational journal of molecular sciences2018
Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 β-lactamase.
Article in International journal of molecular sciences, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 52 citations in OpenAlex.
- Topological metrics as evolutionary and dynamical descriptors of conformational landscapes within protein families.PLoS computational biology · 2026Article
- Dynamic Allostery: Evolution's Double-Edged Sword in Protein Function and Disease.Journal of molecular biology · 2025Review
- Statistical Physics-Based Approaches to Model the Function and Complexation of Disordered Proteins.The journal of physical chemistry. B · 2025Article
- Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.Protein science : a publication of the Protein Society · 2025Article
- Transition Path Sampling Based Free Energy Calculations of Evolution's Effect on Rates in β-Lactamase: The Contributions of Rapid Protein Dynamics to Rate.The journal of physical chemistry. B · 2024Article
- Physiological cost of antibiotic resistance: Insights from a ribosome variant in bacteria.Science advances · 2024Article
- Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory.Journal of chemical theory and computation · 2024Article
- Evidence that the cold- and menthol-sensing functions of the human TRPM8 channel evolved separately.Science advances · 2024Article
- Article
- Customized multiple sequence alignment as an effective strategy to improve performance of Taq DNA polymerase.Applied microbiology and biotechnology · 2023Article
- Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.Protein science : a publication of the Protein Society · 2023Article
- Allosteric inhibition of TEM-1 β lactamase: Microsecond molecular dynamics simulations provide mechanistic insights.Protein science : a publication of the Protein Society · 2023Article
- Design of novel cyanovirin-N variants by modulation of binding dynamics through distal mutations.eLife · 2022Article
- Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all-atom simulations.Protein science : a publication of the Protein Society · 2022Article
- Dynamic allostery highlights the evolutionary differences between the CoV-1 and CoV-2 main proteases.Biophysical journal · 2022Article
- Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.PLoS computational biology · 2022Article
- The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability.International journal of molecular sciences · 2021Article
- Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions.Molecular biology and evolution · 2021Article
- Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?Antibiotics (Basel, Switzerland) · 2020Review
- Rheostat positions: A new classification of protein positions relevant to pharmacogenomics.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2020Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
β-lactamases are enzymes produced by bacteria to hydrolyze β-lactam antibiotics as a common mechanism of resistance. Evolution in such enzymes has been rendering a wide variety of antibiotics impotent, therefore posing a major threat. Clinical and in vitro studies of evolution in TEM-1 β-lactamase have revealed a large number of single point mutations that are responsible for driving resistance to antibiotics and/or inhibitors. The distal locations of these mutations from the active sites suggest that these allosterically modulate the antibiotic resistance. We investigated the effects of resistance driver mutations on the conformational dynamics of the enzyme to provide insights about the mechanism of their long-distance interactions. Through all-atom molecular dynamics (MD) simulations, we obtained the dynamic flexibility profiles of the variants and compared those with that of the wild type TEM-1. While the mutational sites in the variants did not have any direct van der Waals interactions with the active site position S70 and E166, we observed a change in the flexibility of these sites, which play a very critical role in hydrolysis. Such long distance dynamic interactions were further confirmed by dynamic coupling index (DCI) analysis as the sites involved in resistance driving mutations exhibited high dynamic coupling with the active sites. A more exhaustive dynamic analysis, using a selection pressure for ampicillin and cefotaxime resistance on all possible types of substitutions in the amino acid sequence of TEM-1, further demonstrated the observed mechanism. Mutational positions that play a crucial role for the emergence of resistance to new antibiotics exhibited high dynamic coupling with the active site irrespective of their locations. These dynamically coupled positions were neither particularly rigid nor particularly flexible, making them more evolvable positions. Nature utilizes these sites to modulate the dynamics of the catalytic sites instead of mutating the highly rigid positions around the catalytic site.
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