title: Impact of CpG methylation on structure, dynamics and solvation of cAMP DNA responsive element.
abstract: Methylation of CpG motifs in DNA is involved in the control of gene expression and in several other epigenic effects. It suppresses also the immuno-stimulation properties of bacterial or viral DNAs that contain CPGS: However, effects of methylation on the DNA structure and dynamics are not clear. Here we carried out a 10 ns MD simulation, confronted to an NMR analysis, of a hexadecanucleotide with the cAMP responsive element (CRE) DNA methylated at its center: d(GAGATGAmCGTCATCTC)(2) (CREmet). Methylation does not introduce significant structure modification but reduces the dynamics. Molecular mechanics and generalized Born solvation energy calculations showed that the stiffness of CREmet arises from both a restriction of the conformational space by the bulky methyl groups and a folding of DNA around the hydrophobic 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 methylated DNAs to interact with their protein partners-either transcription factors for gene regulation or a Toll-like receptor for immunostimulation-could result from both the obstacle created by methyls, preventing crucial interactions, and the loss of DNA flexibility, reducing its adaptability. Results are discussed in the light of NMR and crystallographic data.
authors.affiliation: Département de Biologie et Pharmacologie Structurales, UMR 8532 CNRS, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94800 Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Derreumaux
authors.forename: M
authors.initials: M
authors.lastname: Chaoui
authors.forename: G
authors.initials: G
authors.lastname: Tevanian
authors.forename: S
authors.initials: S
authors.lastname: Fermandjian
mesh_terms: D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D019175:DNA Methylation; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D012995:Solubility; D013816:Thermodynamics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009841:Oligonucleotides; D004247:DNA; D000242:Cyclic AMP