Abstract
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.