Kinetics and thermodynamics of DNA polymerases with exonuclease proofreading

TL;DR

This paper applies kinetic and thermodynamic analysis to DNA polymerases with exonuclease proofreading, revealing how nucleotide dependence enhances replication fidelity and can reduce errors significantly under physiological conditions.

Contribution

It introduces a theoretical framework that quantifies the impact of nucleotide dependence on proofreading efficiency in DNA polymerases.

Findings

Nucleotide dependence increases replication fidelity.

Up to a hundred-fold reduction in error probability.

Theory matches numerical simulations for T7 and human mitochondrial polymerases.

Abstract

Kinetic theory and thermodynamics are applied to DNA polymerases with exonuclease activity, taking into account the dependence of the rates on the previously incorportated nucleotide. The replication fidelity is shown to increase significantly thanks to this dependence at the basis of the mechanism of exonuclease proofreading. In particular, this dependence can provide up to a hundred-fold lowering of the error probability under physiological conditions. Theory is compared with numerical simulations for the DNA polymerases of T7 viruses and human mitochondria.