5-Methylation of Cytosine in CG:CG Base-Pair Steps: A Physicochemical Mechanism for the Epigenetic Control of DNA Nanomechanics

TL;DR

This study combines density functional theory and structural analysis to reveal how cytosine methylation influences DNA nanomechanics, providing insights into epigenetic regulation mechanisms.

Contribution

It introduces a physicochemical model explaining how methylation modulates DNA stacking energetics and mechanical properties.

Findings

Methylation inhibits CG:CG overtwisting.

Methyl groups soften DNA mechanical modes.

Indirect effects of methylation affect neighboring base steps.

Abstract

Van der Waals density functional theory is integrated with analysis of a non-redundant set of protein-DNA crystal structures from the Nucleic Acid Database to study the stacking energetics of CG:CG base-pair steps, specifically the role of cytosine 5-methylation. Principal component analysis of the steps reveals the dominant collective motions to correspond to a tensile 'opening' mode and two shear 'sliding' and 'tearing' modes in the orthogonal plane. The stacking interactions of the methyl groups globally inhibit CG:CG step overtwisting while simultaneously softening the modes locally via potential energy modulations that create metastable states. Additionally, the indirect effects of the methyl groups on possible base-pair steps neighboring CG:CG are observed to be of comparable importance to their direct effects on CG:CG. The results have implications for the epigenetic control of DNA mechanics.