Computational Studies on the Effects of DNA Methylation on its Structure and Dynamics

Abstract

DNA methylation occurs in CpG dinucleotides when a methyl group is added at the carbon 5 position of the C base ring, and it has an important role in regulating gene expression in higher eukaryotes. It is known that when cytosine bases are methylated, gene is silenced, but the precise role of methylated DNA in this process is still debated, and the mechanism by which methylation affects gene expression remains poorly understood.One hypothesis is that the methylation state of a DNA segment can alter the positions of nucleosomes, which in turn, determine gene expression. Several studies point to a strong link between CpG methylation and nucleosome positioning, but these effects might be indirect because methylation influences the binding of other factors, which could in turn trigger nucleosome repositioning. Because methylation chemically modifies DNA, the methylation status of a DNA sequence could influence its flexibility and, thus, its affinity to the nucleosome. Recent experimental studies suggest that CpG methylation can decrease the ability of DNA to bend into the major groove at the methylated site, and can thereby influence nucleosome positioning.To test the idea that methylation affects the ability of DNA to bend, we performed MD simulations of short DNA segments using an all atom force field. DNA conformations were characterized using the six rigid body base-pair step parameters, the minor groove width and the hybridization state. These properties were measured and compared for dsDNA segments in both the unmethylated and methylated states. In addition, all atom trajectories for both the cases were analyzed to extract a new set of parameters for a coarse grain model for DNA that can now be used to study the effects of methylation in larger DNA systems such as nucleosomes.