At nonzero temperatures, stacked structures of methylated nucleic acid base pairs and microhydrated nonmethylated nucleic acid base pairs are favoredover planar hydrogen-bonded structures: A molecular dynamics simulations study

The dynamic structure of all ten possible nucleic acid (NA) base pairs and methylated NA base pairs hydrated by a small number of water molecules (fro m 1 to 16) was determined by using molecular dynamics simulations in the NV E microcanonical and NVT canonical ensembles with the Cornell force field ( W. D. Cornell, P. Cieplak, C. I. Bayly, I. R.Gould, K. M. Merz, D. M. Fergu son, D. C. Spellmeyer, T. Fox, J. E. Caldwell, P. Kollman, J. Am. Chem. Sec . 1995, 117, 5179). The presence of one water molecule does not affect the structure of any hydrogen-bonded (H-bonded) nonmethylated base pair. An equ al population of H-bonded and stacked structures of adenine adenine, adenin e guanine and adenine thymine pairs is reached if as few as two water molec ules are present, while obtaining equal populations of these structures in the case of adenine cytosine, cytosine thymine, guanine guanine and guanine thymine required the presence of four water molecules, and in the case of guanine cytosine, six. A comparable population of planar, H-bonded and stac ked structures for cytosine cytosine and thymine thymine base pairs was onl y obtained if at least eight water molecules hydrated a pair. Methylation o f bases changed the situation dramatically and stacked structures were favo ured over H-bonded ones even in the absence of water molecules in most case s. Only in the case of methyl cytosine methyl cytosine, methyl guanine meth yl guanine and methyl guanine methyl cytosine pairs were two, two or six wa ter molecules, respectively, needed in order to obtain a comparable populat ion of planar, H-bonded and stacked structures. We believe that these resul ts give clear evidence that the preferred stacked structure of NA base pair s in the microhydrated environment, and also apparently in a regular solven t, is due to the hydrophilic interaction of a small number of water molecul es. In the case of methylated bases, it is also due to the fact that the hy drogen atoms most suitable for the formation of H-bonds have been replaced by a methyl group. A preferred stacked structure is, thus, not due to a hyd rophobic interaction between a large bulk of water molecules and the base p air, as believed.