AbstractEpigenetic marks are modest chemical modifications on DNA and histone proteins that regulate the activation or silencing of genes through modulation of the intermolecular interactions between the DNA strands and the protein machinery. The process is complex and not always well understood. One of the systems studied in greater detail is the epigenetic mark on H3K9: lysine 9 of histone 3. The degree of methylation or acetylation of this histone is linked to silencing or activation of the corresponding gene, but it is not clear which effect each mark has in gene expression. We shed light on this particular methylation process by using density functional theory (DFT) calculations. First, we built a model consisting of a DNA double strand containing three base pairs and a sequence of three amino acids of the histone's tail. Then, we computed the modulation introduced into the intermolecular interactions by each epigenetic modification: from mono‐ to trimethylation and acetylation. The calculations show that whereas acetylation and trimethylation result in a reduction of the DNA‐peptide interaction; non‐, mono‐, and dimethylation increase the intermolecular interactions. Such observations compare well with the findings reported in the literature, and highlight the correlation between the balance of intermolecular forces and biological properties, simultaneously advancing quantum‐mechanical studies of large biochemical systems at molecular level through the use of DFT methods.