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

TL;DR

This study combines experiments and ab initio simulations to demonstrate that quantum proton delocalization in the hydrogen bond network of an enzyme active site significantly influences its catalytic mechanism and isotope effects.

Contribution

It provides new insights into how nuclear quantum effects facilitate proton delocalization in enzyme active sites, impacting enzyme catalysis understanding.

Findings

Quantum proton delocalization stabilizes tyrosine deprotonation.

Extended delocalization occurs with intermediate analogs.

Significant isotope effects on acidity observed.

Abstract

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.