  Enzymes utilize 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.
