An ab initio study of phosphorothioate and phosphorodithioate interactions with sodium cation

The geometries and interaction energies of the sodium-bound nucleic acid backbone analogs Na[(iPrO)(iBuO)PO2], Na[(iPrO)(iBuO)POS(R)], and Na[(iPrO)(iBuO)PS2] have been calculated. The interaction energies are less favorable with increasing sulfur substitution and the destabilizing effect is larger for the second sulfur substitution than it is for the first substitution. The less favorable interaction energies of the phosphorothioate and phosphorodithioate analogs suggest that nucleic acids containing such substitutions should have a lower population of bound cations. This is consistent with widening of the minor groove in B-DNA duplexes containing stereo-regular (R)-phosphorothioate or phosphorodithioate substitutions and increased affinity of sulfur-modified oligonucleotides for proteins.