Sequence effects on energetic and structural properties of phosphorothioate DNA: a molecular modelling study

Phosphorothioate (PS) oligonucleotides constitute a new class of potent drugs, resulting from the replacement of one anionic oxygen of the phosphodiester backbone by one sulphur atom. This replacement confers chirality to the phosphorus atom (PSS or PSR) and alters the energetic, structural and biological properties of B-DNA. These properties were assessed by molecular mechanics calculations on a set of regular sequences, d(YR)8.d(YR)8 and d(RR)8.d(YY)8 (R, purine; Y, pyrimidine). Results indicated: (i) destabilisation of both the PS(R)and the PSS oligomers, the loss of total energy being mainly due to a variation in the electrostatic term; (ii) an additional chirality effect, due to van der Waals and backbone angle energies, larger for PSS oligomers than for PSR oligomers; (iii) a clear sequence effect on stability, particularly from the base immediately preceding the PS group. Even though the PS group alters the stability of oligomers, it does not significantly modify the conformation. Altogether, our molecular modelling data parallel the available experimental data. Our results reveal that sequence effects on the energetic properties of PS oligomers are local and additive. Therefore, studies of the set of the 10 unique double-stranded modified dinucleotide steps included in regular oligomers could be used to predict the behaviour of any double-stranded PS-DNA.