Juliana Gonçalves De Abrantes

This thesis focuses on the investigation of nuclear quantum effects (NQE) on DNA’s stability and photostability, by modulating proton transfer in guanine–cytosine (GC) nucleobases in different contexts.

First, the double-proton transfer between canonical and methylated GC base pairs is analysed under conditions relevant to DNA replication, explicitly including solvent effects and strand separation. By combining density functional theory (DFT) with a nuclear–electronic orbital description of the transferring protons, it is found that NQE significantly enhance proton transfer rates. For the canonical GC pair, the resulting populations of mutagenic species become comparable to spontaneous point-mutation rates in DNA.

Next, photoinduced proton transfer in stacked (GC)2 tetramers is investigated using nonadiabatic surface-hopping dynamics. The simulations reveal an intricate interplay between charge transfer and proton transfer, in which interstrand proton transfer from guanine to cytosine provides an efficient non-radiative decay channel back to the ground state, thereby contributing to DNA photostability.

Finally, NQE on the first excited-state (S1) potential energy surface of the GC base pair are evaluated by combining time-dependent DFT with the nuclear–electronic orbital framework. It is found that NQE strongly stabilise conical intersection structures, steepening the S1 surface along the proton-transfer coordinate. This indicates that NQE facilitate the access to non-radiative decay pathways without altering the proton-coupled electron-transfer mechanism, but assisting photostability mechanisms in DNA. Overall, these studies demonstrate that the quantum nature of the protons in GC hydrogen bonds can play a dual role: under replication conditions, it can increase mutagenic species formation, whereas under photoexcitation the NQE promote an efficient relaxation pathway that leads to DNA photostability.

DNA’s extraordinary resistance to UV-induced damage—essential to the survival of genetic material since prebiotic times—stems from its ability to rapidly and efficiently dissipate electronic excitation energy through damage-free relaxation channels. Multiple decay pathways, at different time scales, have been identified. Yet, the detailed interplay of these competing decay pathways has remained elusive. Using nonadiabatic surface-hopping dynamics at the TDDFT level, we investigate the excited-state behaviour of DNA tetramers composed of stacked guanine–cytosine (GC)2 dimers in alternating and non-alternating sequences. Following photoexcitation, both systems populate a G→C charge-transfer state, with inter-strand proton transfer emerging as the dominant relaxation mechanism. Overall, the simulations reveal a complex network of coupled charge- and proton-transfer events, highlighting the diversity and subtlety of DNA’s excited-state dynamics. These findings provide a mechanistic picture of how stacked bases in DNA efficiently funnel excitation energy back to the ground state.

Methylation of DNA nucleobases is a naturally occurring process in living organisms. Usually, it functions as a gene regulation marker and is connected to inheritable epigenetic effects. However, the methylation of guanine in the O6 position due to external agents disrupts the hydrogen bonding between pairing bases and may have mutagenic effects. In this paper, we use density functional theory (DFT) to investigate the Double Proton Transfer (DPT) between methyl-guanine (mG) and cytosine. We compare the DPT dynamics between mG-C and unmethylated G-C using ab initio nuclear quantum dynamics as implemented in the Nuclear-Electronic Orbital (NEO-DFT) approach, where the protons involved in the transfer are described at the same quantum-mechanical level as the electrons of the system. We find that nuclear quantum effects facilitate the DPT for both systems but increase the rate of point mutations for the canonical base pair G-C more significantly. Noteworthy, when similar calculations are performed in the presence of explicit solvent and strand separation, the DPT mechanism becomes assisted by water, lowering the energy barrier of the reaction.