Molecular dynamics simulation of the effects of cytosine methylation on structure of oligonucleotides

Methylation of the cytosine bases in CpG dinucleotides of DNA is important in many cellular functions including gene regulation, chromosome inactivation, as well as in cancer and other diseases. In this report we investigate the structural effects of methylation of cytosines in CpG sites. Hereditary diseases are frequently caused by mutations in CpG dinucleotides. Aqueous solution molecular dynamics simulations of four mutational hotspot containing DNA octamers were carried out with and without methylated cytosines. No major overall conformational changes were found due to the 5-methyl group of the cytosine base. We also applied potential of mean force calculations to determine the changes in the stacking free energy surface for the deoxyribodinucleoside monophosphate 5-methyl-cytidylyl-3 ' ,5 ' -guanosine compared to the unmethylated form. The 5-methyl group of the cytosine base was found to enhance the base stacking ability. Characteristic features of the free energy surface due to the 5-methyl group were the more pronounced minimum and higher free energy states until the conformations are totally unstacked. Certain local alterations were pronounced in the conformation in the oligonucleotides with methylated CpG dinucleotides. The significance of protein-DNA interactions as a mutation mechanism was discussed. (C) 2001 Elsevier Science B.V. All rights reserved.