Quantum Coulombic Interactions Mediate Free Radical Control in Radical SAM Viperin/RSAD2

Area of Science:

• Biochemistry
• Quantum Chemistry
• Enzymology

Background:

• Radical S-adenosylmethionine (rSAM) enzymes catalyze diverse reactions but their biotechnological use is limited by a poor understanding of radical intermediate control.
• Viperin/RSAD2 is a rare radical SAM enzyme found in humans, making it a key subject for studying radical control mechanisms.

Purpose of the Study:

• To elucidate the mechanism of radical control in the rSAM enzyme Viperin/RSAD2.
• To identify the role of quantum Coulombic interactions in stabilizing reactive radical intermediates.

Main Methods:

• Employed molecular dynamics and high-level quantum mechanical/molecular mechanics (QM/MM) calculations.
• Utilized multistate broken-symmetry QM/MM to analyze catalytic mechanisms and radical stabilization.

Main Results:

• Identified an unusual metastable deprotonated ribose radical intermediate during catalysis.
• Demonstrated that spin-charge exchange-correlation interactions (a quantum Coulombic effect) thermodynamically stabilize this radical intermediate.
• Quantified the stabilization, showing the radical is 2-6 pKa units more acidic than closed-shell ribose.

Conclusions:

• Quantum Coulombic interactions are crucial for free radical control in Viperin/RSAD2.
• This mechanism of stabilizing reactive radical intermediates may be universal across radical enzymes.
• Findings open new possibilities for enzyme engineering and biotechnological applications.