Proton Transfer Causing DNA Point Mutations: Quantum Tunneling Effects in G-C Base Pairs Revealed

• A study published in the international journal PCCP (Physical Chemistry Chemical Physics) models the proton transfer pathways and quantum tunneling rates during Watson-Crick tautomerism in DNA A-T and G-C base pairs, utilizing Density Functional Theory (DFT) and a machine learning-based Nudged Elastic Band (ML-NEB) algorithm.
• The research physically demonstrates that proton transfer in A-T base pairs is highly unstable due to an extremely low reverse-reaction barrier, making the occurrence of mutations during the replication process highly improbable.
• In G-C base pairs, a high quantum tunneling correction value was observed, providing the first physical proof that the mutant form (G-C) possesses a biological lifespan sufficient to be misread as an error by the human DNA replication machinery (replisome).

[Quantum Biology Society]

The phenomenon wherein protons shift positions within the hydrogen bonds of DNA—the carrier of an organism's genetic information—can induce transient but lethal point mutations. Known as tautomerism, this process has long been identified as a potential root cause of genetic variation and oncogenesis. A recent study published in Physical Chemistry Chemical Physics (PCCP) has combined pure quantum mechanical modeling (DFT) with machine learning techniques to precisely calculate the energy barriers of double proton transfer occurring within A-T and G-C base pairs. This significant physicochemical research was conducted by L. Slocombe, J. S. Al-Khalili, and M. Sacchi of the University of Surrey, UK.

■ Instantly Collapsing A-T Tautomers vs. Surviving G-C Tautomers

The research team analyzed the energy landscape as the hydrogen bond structure shifts from the standard (amino-keto) to the mutant (imino-enol) form, using Density Functional Theory (DFT) and a machine learning-based Nudged Elastic Band (ML-NEB) algorithm. The results revealed that in A-T base pairs, although a quantum tunneling effect transitioning toward the mutant A*-T* state was observed, the reverse-reaction barrier was virtually nonexistent. Consequently, the state could not be maintained and immediately collapsed back into its original standard form.

The situation was different for G-C base pairs. Beyond the classical reaction where protons cross the barrier using only thermal energy at room temperature, it was confirmed that wave-like movement via quantum tunneling contributes decisively to the formation of mutant populations. The team mathematically proved that the G-C mutant (G*-C*), which showed a significantly high tunneling correction value, possesses a lifespan long enough to reach the human replisome, suggesting a high probability of solidifying into a permanent point mutation.

■ Genetic Stability Governed by Physical Laws

This study is a landmark achievement, demonstrating that complex DNA mutations occurring during the most critical replication processes of life are not merely the result of random thermal fluctuations, but are substantially controlled and shaped by the microscopic physical laws of quantum tunneling dynamics. By providing objective data on how the wave-like nature of protons physically threatens the fidelity of genetic information replication, this study underscores the importance of a quantum biological approach in future research regarding DNA damage and mutation-related diseases.

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https://pubs.rsc.org/en/content/articlehtml/2021/cp/d0cp05781a