Coupled Binuclear Copper Sites in Biology: An Experimentally-Calibrated Computational Perspective

Area of Science:

• Biochemistry
• Bioinorganic Chemistry
• Computational Chemistry

Background:

• Coupled-binuclear copper (CBC) enzymes feature a [Cu2O2] catalytic core.
• These enzymes perform challenging regioselective oxidations of phenols.
• Previous understanding of CBC enzyme reactivity factors was incomplete.

Purpose of the Study:

• To elucidate the initial mechanistic steps of ortho-hydroxylation catalyzed by tyrosinase (Ty).
• To review and integrate experimental and computational findings on CBC enzyme reactivity.
• To explore structure-function correlations across CBC enzyme classes.

Main Methods:

• Synergy of spectroscopy and kinetic experiments.
• State-of-the-art computational methods (QM/MM, WFT).
• Calibrated theoretical calculations validated by experimental data.

Main Results:

• A conclusive mechanistic picture of tyrosinase's initial ortho-hydroxylation stages was established.
• Definitive insight into the catalytic reaction coordinate was achieved.
• Previous structure-function correlation efforts were critically reviewed.

Conclusions:

• Mechanistic understanding across CBC enzyme classes can reveal structure-function correlations.
• Potential for utilizing the [Cu2O2] core in materials and biocatalysis.
• Advanced computational and experimental synergy is key to understanding metalloenzyme catalysis.