Quantum Tunnelling Effects in the Guanine-Thymine Wobble Misincorporation via Tautomerisation

The misincorporation of a non-complimentary DNA base in the polymerase active site is a critical source of replication errors that can lead to genetic mutations. In this work, we model the mechanism of wobble mispairing and the subsequent rate of misincorporation errors by coupling first-principles quantum chemistry calculations to an open quantum systems master equation. This methodology allows us to accurately calculate the proton transfer between bases, allowing the misincorporation and formation of mutagenic tautomeric forms of DNA bases. Our quantum mechanic model predicts the existence of a short-lived ``tunnelling-ready" configuration along the wobble reaction pathway, effectively compressing the energy barrier for this reaction and dramatically increasing the rate of mismatch formation by a hundredfold. Further, we calculate rates of genetic error formation that are in excellent agreement with experimentally observed mutation rates, demonstrating that quantum tunnelling plays a critical role in determining the transcription error frequency of the polymerase.