Nanoscale Properties of the Methylation in GpC Dinucleotide Systems

Abstract

AbstractThe incorporation of a methyl group to DNA nucleotides (methylation) is a well known phenomenon in epigenetic regulation. Methylation can result in gene silencing. Here we investigate the electronic properties of cytosine methylation in different DNA systems using first‐principles density functional theory calculations. Specifically, four systems are investigated consisting of two stacked base pairs, including the deoxyribose‐phosphate backbone. These four systems are the unmethylated GpC‐CpG, the single methylated GpC‐mCpG, the double symmetrical methylated GpCm‐mCpG, and the quadruple symmetrical GpCmm‐mmCpG. Single base‐pair cases are also considered with and without the deoxyribose‐phosphate backbone (with: pG‐pC, pG‐pCm, and pG‐pCmm; without: G−C, G−Cm, and G‐Cmm). These structures are relaxed using the conjugate gradient method. Nanoscale properties, such as the electronic density of states, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) wave functions, charge Mulliken population, hydrogen bond energy, binding energy, and dipole moments between unmethylated and methylated relaxed structures are obtained and compared. These results demonstrate that the deoxyribose‐phosphate backbone plays a crucial role in the spatial distribution of HOMO and LUMO wave functions in the stacked systems modulating reactivity and stability. Cytosine methylation on the GpC‐CpG system results in a stabilization effect. Dipole moment modification in the studied systems could favor specific protein‐DNA interactions due to the methyl group non‐polarity, producing hydrophobic DNA regions. These findings suggest specific rules of interaction between methylated regions and gene silencing elements at the nanoscale level.