Direct Proton-Coupled Electron Transfer between Interfacial Tyrosines in Ribonucleotide Reductase

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Ribonucleotide reductase (RNR) is essential for DNA synthesis and repair.
• The mechanism involves radical transfer across protein subunits via proton-coupled electron transfer (PCET).
• A critical step is the interfacial PCET between Y356 (β subunit) and Y731 (α subunit) in E. coli RNR.

Purpose of the Study:

• To investigate the PCET reaction mechanism between Y356 and Y731 across an aqueous interface.
• To determine the feasibility of water-mediated versus direct PCET pathways.

Main Methods:

• Classical molecular dynamics simulations.
• Quantum mechanical/molecular mechanical (QM/MM) free energy simulations.

Main Results:

• The water-mediated double proton transfer mechanism is thermodynamically and kinetically unfavorable.
• A direct PCET mechanism between Y356 and Y731 is feasible when Y731 is oriented towards the interface.
• This direct pathway exhibits a low free energy barrier and is facilitated by water hydrogen bonding to both tyrosines.

Conclusions:

• The direct PCET mechanism is the likely pathway for radical transfer across the aqueous interface in E. coli RNR.
• Computational simulations provide fundamental insights into radical transfer mechanisms at aqueous interfaces.