Proton transfer in methylated G-C: nuclear quantum effects and water-assisted hopping

Area of Science:

• Computational Chemistry
• Molecular Biophysics
• Epigenetics

Background:

• DNA methylation is a key epigenetic mechanism regulating gene expression.
• O6-methylation of guanine by external agents can disrupt base pairing and lead to mutations.
• Understanding the dynamics of proton transfer in DNA base pairs is crucial for assessing mutagenicity.

Purpose of the Study:

• To investigate the double proton transfer (DPT) dynamics between methyl-guanine (mG) and cytosine.
• To compare DPT in mG-C pairs versus canonical G-C pairs using quantum mechanical methods.
• To explore the influence of nuclear quantum effects and solvent on DPT mechanisms.

Main Methods:

• Density Functional Theory (DFT) calculations were employed.
• Ab initio nuclear quantum dynamics, using the nuclear-electronic orbital (NEO-DFT) approach, simulated proton transfer.
• Calculations were performed for isolated base pairs and in the presence of explicit solvent and strand separation.

Main Results:

• Nuclear quantum effects were found to facilitate DPT in both mG-C and G-C pairs.
• The rate of point mutations was significantly increased for the canonical G-C pair due to nuclear quantum effects.
• Explicit solvent and strand separation assisted the DPT mechanism, lowering the reaction's energy barrier.

Conclusions:

• Quantum mechanical treatments of protons are essential for accurately modeling DNA base pair dynamics.
• O6-methylguanine's mutagenic potential is influenced by proton transfer dynamics, modulated by quantum effects and solvation.
• Water plays a significant role in facilitating proton transfer reactions within DNA, potentially impacting mutagenesis.