Impact of CpG methylation on structure, dynamics and solvation of cAMP DNAresponsive element

Methylation of CpG motifs in DNA is involved in the control of gene express ion and in several other epigenic effects, It suppresses also the immunosti mulation properties of bacterial or viral DNAs that contain CpGs, However, effects of methylation on the DNA structure and dynamics are not clear. Her e we carried out a 10 ns MD simulation, confronted to an NMR analysis, of a hexadecanucleotide with the cAMP responsive element (CRE) DNA methylated a t its center: d(GAGATGAmCGTCATCTC)(2) (CREmet), Methylation does not introd uce significant structure modification but reduces the dynamics. Molecular mechanics end generalized Born solvation energy calculations showed that th e stiffness of CREmet arises from both a restriction of the conformational space by the bulky methyl groups and a folding of DNA around the hydrophobi c methyls. The latter effect is favored when the GpA steps belonging to the TGA binding half-sites adopt the BII conformation. The inability of the me thylated DNAs to interact with their protein partners-either transcription factors for gene regulation or a Toll-like receptor for Immunostimulation-c ould result from both the obstacle created by methyls, preventing crucial i nteractions, and the loss of DNA flexibility, reducing its adaptability, Re sults are discussed in the light of NMR and crystallographic data.