Mechanistic Insights into Radical-Mediated Oxidation of Tryptophan from ab Initio Quantum Chemistry Calculations and QM/MM Molecular Dynamics Simulations

An assessment of
the mechanisms of •OH and •OOH
radical-mediated oxidation of tryptophan was performed
using density functional theory calculations and ab initio plane-wave
Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics simulations.
For the •OH reactions, addition to the pyrrole ring
at position 2 is the most favored site with a barrierless reaction
in the gas phase. The subsequent degradation of this adduct through
a H atom transfer to water was intermittently observed in aqueous-phase
molecular dynamics simulations. For the •OOH reactions,
addition to the pyrrole ring at position 2 is the most favored pathway,
in contrast to the situation in the model system ethylene, where concerted
addition to the double bond is preferred. From the •OOH position 2 adduct QM/MM simulations show that formation of oxy-3-indolanaline
occurs readily in an aqueous environment. The observed transformation
starts from an initial rupture of the O–O bond followed by
a H atom transfer with the accompanying loss of an •OH radical to solution. Finally, classical molecular dynamics simulations
were performed to equate observed differential oxidation rates of
various tryptophan residues in monoclonal antibody fragments. It was
found that simple parameters derived from simulation correlate well
with the experimental data.