Probing the role of structural water in a duplex oligodeoxyribonucleotide containing a water-mimicking base analog

Molecular dynamics simulations were performed on models of the dodecamer DNA double-stranded segment, [d(CGCGAATTCGCG)](2), in which each of the adenine residues, individually or jointly, was replaced by the water-mimicking analog 2'-deoxy-7-(hydroxy-methyl)-7-deazaadenosine (hm(7)c(7)dA) [Rockhill, J.K., Wilson,S.R. and Gumport,R.I. (1996) J. Am. Chem. Soc.,118, 10065-10068]. The simulations, when compared with those of the dodecamer itself, show that incorporation of the analog affects neither the overall DNA structure nor its hydrogen-bonding and stacking interactions when it replaces a single individual base. Furthermore, the water molecules near the bases in the singly-substituted oligonucleotides are similarly unaffected. Double substitutions lead to differences in all the aforementioned parameters with respect to the reference sequence. The results suggest that the analog provides a good mimic of specific 'ordered' water molecules observed in contact with DNA itself and at the interface between protein and DNA in specific complexes.