ArticleJournal of the American Chemical Society2016
A Critical Test of the Electrostatic Contribution to Catalysis with Noncanonical Amino Acids in Ketosteroid Isomerase.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 132 citations in OpenAlex.
- Towards next generation enzyme mimics through local electric field control in organic cage catalysts.Chemical science · 2026Article
- Catalytic Promiscuity and Cascade Reaction Mechanism of Ketosteroid Isomerases for Addition Reactions of Cyclic Enones.Nature communications · 2026Article
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- Peeling tape produces strong electric fields via stick-slip friction that drive chemical reactions.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Spatially Regulated Electrical Forces for Biological Catalysis.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Noncanonical Amino Acids: Bringing New-to-Nature Functionalities to Biocatalysis.Chemical reviews · 2024Review
- An efficient pyrrolysyl-tRNA synthetase for economical production of MeHis-containing enzymes.Faraday discussions · 2024Article
- Noncanonical Amino Acids in Biocatalysis.Chemical reviews · 2024Review
- Long-range electrostatic effects from intramolecular Lewis acid binding influence the redox properties of cobalt-porphyrin complexes.Chemical science · 2024Article
- Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields.Journal of the American Chemical Society · 2024Article
- Electrostatics as a Guiding Principle in Understanding and Designing Enzymes.Journal of chemical theory and computation · 2024Review
- Hydrophobicity-Based Force Field In Enzymes.ACS omega · 2024Article
- Theoretical Improvements in Enzyme Efficiency Associated with Noisy Rate Constants and Increased Dissipation.Entropy (Basel, Switzerland) · 2024Article
- Free Energy Profile Decomposition Analysis for QM/MM Simulations of Enzymatic Reactions.Journal of chemical theory and computation · 2023Article
- Engineering mutually orthogonal PylRS/tRNA pairs for dual encoding of functional histidine analogues.Protein science : a publication of the Protein Society · 2023Article
- Protein Dynamics and Enzymatic Catalysis.The journal of physical chemistry. B · 2023Review
- Engineering enzyme activity using an expanded amino acid alphabet.Protein engineering, design & selection : PEDS · 2023Article
- Automated Variable Electric-Field DFT Application for Evaluation of Optimally Oriented Electric Fields on Chemical Reactivity.The Journal of organic chemistry · 2023Article
- Proton transfer reactions: From photochemistry to biochemistry and bioenergetics.BBA advances · 2023Article
- Setting Boundaries for Statistical Mechanics.Molecules (Basel, Switzerland) · 2022Review
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2 authors at 1 institution in 1 country.
Funding
Abstract
The vibrational Stark effect (VSE) has been used to measure the electric field in the active site of ketosteroid isomerase (KSI). These measured fields correlate with ΔG(⧧) in a series of conventional mutants, yielding an estimate for the electrostatic contribution to catalysis (Fried et al. Science 2014, 346, 1510-1513). In this work we test this result with much more conservative variants in which individual Tyr residues in the active site are replaced by 3-chlorotyrosine via amber suppression. The electric fields sensed at the position of the carbonyl bond involved in charge displacement during catalysis were characterized using the VSE, where the field sensitivity has been calibrated by vibrational Stark spectroscopy, solvatochromism, and MD simulations. A linear relationship is observed between the electric field and ΔG(⧧) that interpolates between wild-type and more drastic conventional mutations, reinforcing the evaluation of the electrostatic contribution to catalysis in KSI. A simplified model and calculation are developed to estimate changes in the electric field accompanying changes in the extended hydrogen-bond network in the active site. The results are consistent with a model in which the O-H group of a key active site tyrosine functions by imposing a static electrostatic potential onto the carbonyl bond. The model suggests that the contribution to catalysis from the active site hydrogen bonds is of similar weight to the distal interactions from the rest of the protein. A similar linear correlation was also observed between the proton affinity of KSI's active site and the catalytic rate, suggesting a direct connection between the strength of the H-bond and the electric field it exerts.
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