Effect of phosphorothioate chirality on the grooves of DNA double helices: A molecular dynamics study

Phosphorothioate oligonucleotides (PS-ODNs) have gained considerable attention in drug therapy, primarily as potent antisense or antigene oligomers, which bind to specific DNA or mRNA sequences and lead to transcriptional or translational arrest. These are obtained by substituting one of the anionic oxygen of the phosphate group by a sulfur atom, which introduces chirality to the phosphorus atom of the DNA backbone. In this molecular dynamics simulation study, structural parameters like groove widths, environmental parameters like hydration or cation binding, and electrostatic energy surfaces of both the chiral forms of DNA/PS-DNA duplexes were assessed and compared with that of a normal DNA. Results indicate that, PS-S form with its sulfur atoms facing the minor groove has a widened minor groove, while the scenario is reverse for the PS-R form. Further analysis reveals the existence of several factors like large van der Waals radius of sulfur and the effect it has on its neighboring hydration pattern along with the net electrostatic environment, influencing such structural alterations. This also indicates, for the first time, the effect of absolute phosphorothioate chirality on the global structure of a DNA/PS-DNA hybrid that otherwise resembles a regular B-DNA structure.