Quantum and classical effects in DNA point mutations: Watson-Crick tautomerism in AT and GC base pairs

• Published in: Physical chemistry chemical physics : PCCP 2021-02, Vol.23 (7), p.4141-415
• Main Authors: Slocombe, L, Al-Khalili, J. S, Sacchi, M
• Format: Article
• Language: English
• Subjects: Base Pairing; Density Functional Theory; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; Hydrogen Bonding; Hydrogen bonds; Isomerism; Machine learning; Models, Chemical; Mutation; Point Mutation; Protons; Thermodynamics
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/d0cp05781a

Proton transfer along the hydrogen bonds of DNA can lead to the creation of short-lived, but biologically relevant point mutations that can further lead to gene mutation and, potentially, cancer. In this work, the energy landscape of the canonical A-T and G-C base pairs (standard, amino-keto) to tautomeric A*-T* and G*-C* (non-standard, imino-enol) Watson-Crick DNA base pairs is modelled with density functional theory and machine-learning nudge-elastic band methods. We calculate the energy barriers and tunnelling rates of hydrogen transfer between and within each base monomer (A, T, G and C). We show that the role of tunnelling in A-T tautomerisation is statistically unlikely due to the presence of a small reverse reaction barrier. On the contrary, the thermal populations of the G*-C* point mutation could be non-trivial and propagate through the replisome. For the direct intramolecular transfer, the reaction is hindered by a substantial energy barrier. However, our calculations indicate that tautomeric bases in their monomeric form have remarkably long lifetimes. Proton transfer along the hydrogen bonds of DNA can lead to the creation of short-lived, but biologically relevant point mutations that can further lead to gene mutation and, potentially, cancer.