Quantum delocalization of protons in the hydrogen-bond network of an enzyme active site

Lu Wang, Stephen D. Fried, Steven G. Boxer, Thomas E. Markland

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Enzymes use protein architectures to create highly specialized structural motifs that can greatly enhance the rates of complex chemical transformations. Here, we use experiments, combined with ab initio simulations that exactly include nuclear quantum effects, to show that a triad of strongly hydrogen-bonded tyrosine residues within the active site of the enzyme ketosteroid isomerase (KSI) facilitates quantum proton delocalization. This delocalization dramatically stabilizes the deprotonation of an active-site tyrosine residue, resulting in a very large isotope effect on its acidity. When an intermediate analog is docked, it is incorporated into the hydrogen-bond network, giving rise to extended quantum proton delocalization in the active site. These results shed light on the role of nuclear quantum effects in the hydrogen-bond network that stabilizes the reactive intermediate of KSI, and the behavior of protons in biological systems containing strong hydrogen bonds.

Original languageEnglish (US)
Pages (from-to)18454-18459
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number52
DOIs
StatePublished - Dec 30 2014

Fingerprint

Protons
Hydrogen
Catalytic Domain
Ketosteroids
Isomerases
Enzymes
Tyrosine
Isotopes
Proteins

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Ab initio path integral molecular dynamics
  • Enzyme
  • Hydrogen bonding
  • Nuclear quantum effects
  • Proton delocalization

Cite this

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abstract = "Enzymes use protein architectures to create highly specialized structural motifs that can greatly enhance the rates of complex chemical transformations. Here, we use experiments, combined with ab initio simulations that exactly include nuclear quantum effects, to show that a triad of strongly hydrogen-bonded tyrosine residues within the active site of the enzyme ketosteroid isomerase (KSI) facilitates quantum proton delocalization. This delocalization dramatically stabilizes the deprotonation of an active-site tyrosine residue, resulting in a very large isotope effect on its acidity. When an intermediate analog is docked, it is incorporated into the hydrogen-bond network, giving rise to extended quantum proton delocalization in the active site. These results shed light on the role of nuclear quantum effects in the hydrogen-bond network that stabilizes the reactive intermediate of KSI, and the behavior of protons in biological systems containing strong hydrogen bonds.",
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Quantum delocalization of protons in the hydrogen-bond network of an enzyme active site. / Wang, Lu; Fried, Stephen D.; Boxer, Steven G.; Markland, Thomas E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 52, 30.12.2014, p. 18454-18459.

Research output: Contribution to journalArticle

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AU - Fried, Stephen D.

AU - Boxer, Steven G.

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AB - Enzymes use protein architectures to create highly specialized structural motifs that can greatly enhance the rates of complex chemical transformations. Here, we use experiments, combined with ab initio simulations that exactly include nuclear quantum effects, to show that a triad of strongly hydrogen-bonded tyrosine residues within the active site of the enzyme ketosteroid isomerase (KSI) facilitates quantum proton delocalization. This delocalization dramatically stabilizes the deprotonation of an active-site tyrosine residue, resulting in a very large isotope effect on its acidity. When an intermediate analog is docked, it is incorporated into the hydrogen-bond network, giving rise to extended quantum proton delocalization in the active site. These results shed light on the role of nuclear quantum effects in the hydrogen-bond network that stabilizes the reactive intermediate of KSI, and the behavior of protons in biological systems containing strong hydrogen bonds.

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