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

Phosphorothioate (PS) oligonucleotides constitute a new class of potent dru gs, resulting from the replacement of one anionic oxygen of the phosphodies ter backbone by one sulphur atom. This replacement confers chirality to the phosphorus atom (PSS or PSR) and alters the energetic, structural and biol ogical properties of B-DNA. These properties were assessed by molecular mec hanics 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) destab ilisation of both the PSR and the PSS oligomers, the loss of total energy b eing mainly due to a variation in the electrostatic term; (ii) an additiona l chirality effect, due to van der Waals and backbone angle energies, large r for PSS oligomers than for PSR oligomers; (iii) a clear sequence effect o n stability, particularly from the base immediately preceding the PS group. Even though the PS group alters the stability of oligomers, it does not si gnificantly modify the conformation. Altogether, our molecular modelling da ta parallel the available experimental data. Our results reveal that sequen ce effects on the energetic properties of PS oligomers are local and additi ve. 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.