Mg²⁺ Catalyzes Nonenzymatic RNA Primer Extension through a Concerted Outer-Sphere Mechanism

Area of Science:

• Origin of Life Studies
• Biochemistry
• Computational Chemistry

Background:

• Nonenzymatic RNA replication is a vital step in abiogenesis.
• Template-directed RNA primer extension is a model system for studying early replication.
• The catalytic mechanism of divalent metal ions, like Mg2+, remains unclear.

Purpose of the Study:

• To investigate the catalytic role of Mg2+ in nonenzymatic RNA primer extension.
• To elucidate the mechanism by which Mg2+ facilitates the reaction.

Main Methods:

• Classical molecular dynamics simulations.
• Hybrid quantum mechanics/molecular mechanics (QM/MM) calculations.
• Free energy landscape analysis along reaction coordinates.

Main Results:

• Mg2+ significantly lowers the pKa of the 3 '-OH group of the RNA primer.
• Mg2+ coordination reduces the likelihood of unproductive O2 ' attack.
• A preferred catalytic mechanism involving outer-sphere Mg2+ coordination and concerted proton transfer was identified.

Conclusions:

• Mg2+ plays both structural and electronic roles in catalyzing RNA primer extension.
• Understanding Mg2+ catalysis provides insights for designing molecules to enhance nonenzymatic replication.
• This work advances our understanding of early RNA replication mechanisms relevant to the origin of life.