Metal Ion Dynamics in DNA Polymerase Function

DNA polymerases rely on divalent metal ions to catalyse the nucleotidyl transfer reaction and to ensure high fidelity during genome replication and repair. The classical two-metal-ion mechanism positions one metal ion (site A) to activate the 3′-hydroxyl of the primer terminus and a second metal ion (site B) to stabilise the negative charge on the incoming deoxynucleoside triphosphate. Recent structural and kinetic studies have revealed a transient third metal ion that appears during the phosphoryl transfer step, fine-tuning the transition-state energetics and influencing both reaction rate and error discrimination. Substitution of magnesium by alternative divalent cations such as manganese, cobalt or cadmium can alter base‐pair selectivity and proofreading efficiency by modifying metal-ligand geometry, perturbing the pKa of active-site ligands and changing the residence time of substrates. Time-resolved crystallography, cryo-electron microscopy and molecular dynamics simulations have shed light on conformational transitions of polymerase domains in response to metal binding and dissociation. These insights are informing the design of novel inhibitors and metal-based modulators with potential applications in antiviral therapies, biotechnology and precision genome editing.

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Metal Ion Dynamics in DNA Polymerase Function publication trend

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Technical terms

Divalent cation: A metal ion with a +2 charge (e.g. Mg2+, Mn2+, Co2+) that serves as an essential cofactor in polymerase catalysis.

Two-metal-ion mechanism: A catalytic strategy in which one metal activates the primer 3′-hydroxyl and a second metal stabilises the incoming nucleotide’s triphosphate.

Third metal ion: A transient divalent cation observed in time-resolved studies that transiently coordinates the transition state during phosphoryl transfer.

Proofreading: The 3′→5′ exonuclease activity of some DNA polymerases that excises misincorporated nucleotides to enhance replication fidelity.

Conformational dynamics: Structural rearrangements of polymerase domains (fingers, palm, thumb) that accompany nucleotide binding, catalysis and translocation.

References

1. Different Divalent Cations Alter the Kinetics and Fidelity of DNA Polymerases*. Journal of Biological Chemistry (2016).
2. On the enzymatic basis for mutagenesis by manganese.. Journal of Biological Chemistry (1983).
3. The effect of different divalent cations on the kinetics and fidelity of Bacillus stearothermophilus DNA polymerase. AIMS Biophysics (2018).