Atom Tunneling in the Hydroxylation Process of Taurine/$\alpha$-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations

TL;DR

This study uses QM/MM simulations to reveal that hydrogen tunneling significantly accelerates the hydroxylation process in TauD dioxygenase, providing insights into its catalytic mechanism and kinetic isotope effects.

Contribution

It is the first to demonstrate quantum tunneling's role in the hydrogen transfer step of TauD dioxygenase using combined quantum mechanics/molecular mechanics simulations.

Findings

Quantum tunneling increases the rate constant by a factor of 40 at 5°C.

The reaction involves a concerted mechanism with simultaneous electron and hydrogen transfer.

The calculated kinetic isotope effect (KIE) is close to 60, matching experimental data.

Abstract

TauD dioxygenase is one of the most studied $\alpha$-ketoglutarate dependent dioxygenases ($\alpha$KGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the $\alpha$KGDs, the hydrogen transfer process, by a QM/MM approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe=O cofactor. We found quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5\textcelsius{}. As a consequence a quite high KIE value of close to 60 is obtained, which is consistent with the experimental value.