H.-O. Bertrand (1), B. Hartmann (2), and S. Fermandjian (3)
1 : Molecular Simulations Inc., Parc Club Orsay Université, 20 rue Jean Rostand, 91893 Orsay Cedex, FRANCE.
2 : Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, UPR CNRS 9080, 13 rue Pierre et Marie Curie, 75005 Paris, FRANCE.
3 : Département de Biologie Structurale, Institut Gustave Roussy, UMR CNRS 1772, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, FRANCE.

Phosphorothioate oligonucleotides (PS-Oligomers) constitute a new class of potent drugs, resulting from the replacement of anionic oxygens of the phosphodiester backbone by sulphur atoms. This replacement confers chirality to the phosphorus atom (PSS or PSR). The influence of the substitution on energetic, structural and biological properties of B-DNA, was assessed by molecular mechanics calculations using a set of regular sequences, d(YR)8.d(YR)8 and d(RR)8.d(YY)8 (R:purine ; Y:pyrimidine). Analysis of energetic data indicated a  significant decrease of stability for all the PS-oligomers with respect to the PO-oligomers, used for a sake of comparison. PSR-oligomers were found more stable than PSS-oligomers underlining the effect of the chirality. The total loss of energy is due to the electrostatic component. The stability is found strongly dependent on the nature of the 5’ base flanking the PS-group, reflecting a sequence effect. However, the PS-group does not significantly alter the conformation. All together modelling results are conform to available experimental data and can be used to predict a general sequence effect in PS-DNA.

Key-words : Phosphorothioate B-DNA, Molecular mechanics.