PMID- 25494783 OWN - NLM STAT- MEDLINE DCOM- 20150806 LR - 20151119 IS - 1089-7690 (Electronic) IS - 0021-9606 (Linking) VI - 141 IP - 22 DP - 2014 Dec 14 TI - Hydration properties of natural and synthetic DNA sequences with methylated adenine or cytosine bases in the R.DpnI target and BDNF promoter studied by molecular dynamics simulations. PG - 22D512 LID - 10.1063/1.4897525 [doi] AB - Adenine and cytosine methylation are two important epigenetic modifications of DNA sequences at the levels of the genome and transcriptome. To characterize the differential roles of methylating adenine or cytosine with respect to their hydration properties, we performed conventional MD simulations and free energy perturbation calculations for two particular DNA sequences, namely the brain-derived neurotrophic factor (BDNF) promoter and the R.DpnI-bound DNA that are known to undergo methylation of C5-methyl cytosine and N6-methyl adenine, respectively. We found that a single methylated cytosine has a clearly favorable hydration free energy over cytosine since the attached methyl group has a slightly polar character. In contrast, capping the strongly polar N6 of adenine with a methyl group gives a slightly unfavorable contribution to its free energy of solvation. Performing the same demethylation in the context of a DNA double-strand gave quite similar results for the more solvent-accessible cytosine but much more unfavorable results for the rather buried adenine. Interestingly, the same demethylation reactions are far more unfavorable when performed in the context of the opposite (BDNF or R.DpnI target) sequence. This suggests a natural preference for methylation in a specific sequence context. In addition, free energy calculations for demethylating adenine or cytosine in the context of B-DNA vs. Z-DNA suggest that the conformational B-Z transition of DNA transition is rather a property of cytosine methylated sequences but is not preferable for the adenine-methylated sequences investigated here. FAU - Shanak, Siba AU - Shanak S AD - Zentrum fur Bioinformatik, Universitat des Saarlandes, P.O. Box 15 11 50, 66123 Saarbrucken, Germany. FAU - Helms, Volkhard AU - Helms V AD - Zentrum fur Bioinformatik, Universitat des Saarlandes, P.O. Box 15 11 50, 66123 Saarbrucken, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Chem Phys JT - The Journal of chemical physics JID - 0375360 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (DNA, B-Form) RN - 0 (DNA, Z-Form) RN - 059QF0KO0R (Water) RN - 6R795CQT4H (5-Methylcytosine) RN - 9007-49-2 (DNA) RN - EC 3.1.21.- (endodeoxyribonuclease DpnI) RN - EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific) RN - JAC85A2161 (Adenine) RN - W7IBY2BGAX (6-methyladenine) SB - IM MH - 5-Methylcytosine/*analysis MH - Adenine/*analogs & derivatives/analysis MH - Brain-Derived Neurotrophic Factor/genetics MH - DNA/*chemistry/genetics MH - DNA Methylation MH - DNA, B-Form/chemistry/genetics MH - DNA, Z-Form/chemistry/genetics MH - Deoxyribonucleases, Type II Site-Specific/genetics MH - *Molecular Dynamics Simulation MH - Promoter Regions, Genetic MH - Thermodynamics MH - Water/*chemistry EDAT- 2014/12/17 06:00 MHDA- 2015/08/08 06:00 CRDT- 2014/12/16 06:00 PHST- 2014/12/16 06:00 [entrez] PHST- 2014/12/17 06:00 [pubmed] PHST- 2015/08/08 06:00 [medline] AID - 10.1063/1.4897525 [doi] PST - ppublish SO - J Chem Phys. 2014 Dec 14;141(22):22D512. doi: 10.1063/1.4897525.