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

61 Scopus citations


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
Issue number52
StatePublished - Dec 30 2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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

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