Properties of phosphorothioate DNA analogs. An ab initio study of prototype model linkages derived from dimethyl-phosphate anion

Ab initio HF and MP2 calculations on prototype model linkages of phosphorothioate DNA backbones illuminate the effects of phosphorothioation on electronic and structural properties of DNA backbone. The replacement of a bridging oxygen atom by sulfur in the phosphodiester linkage is energetically favored over that of replacement of a non-bridging oxygen atom. In phosphorothioate derivatives containing the P(OS)_nb moiety, the non-bridging oxygen atom always bears a higher negative charge than the non-bridging sulfur. Additional calculations on protonated (neutral) adducts suggest that phosphorothioation of the phosphodiester linkage lowers its proton affinity. Moreover, protonation of the non-bridging oxygen atom at phosphorous is favored over the protonation of the non-bridging sulfur atom for linkages containing the P(OS)_nb moiety. The ab initio calculated structural parameters are compared to the available crystallographic data of small phosphorothioate molecules and phosphorothioate oligodeoxynucleotides. These results have implications upon the biological activity of phosphorothioate DNA analogs.