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

Abstract

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.

The Study of Naphthoquinones and Their Complexes with DNA by Using Raman Spectroscopy and Surface Enhanced Raman Spectroscopy: New Insight into Interactions of DNA with Plant Secondary Metabolites

“…In the spectrum of modified DNA by 1,4-naphthoquinone and plumbagin, this band is slightly lower than in the comparison in the spectrum of the DNA modified by binaphthoquinone, juglone, and lawsone which is in good agreement with the data above-mentioned. The band at 1073 cm −1 is partly related to the vibration of the sugar-phosphate backbone (probably electrostatic interaction of the phosphate group) [79–82], but it especially corresponds with the vibrations to the contribution of the naphthoquinones measured in the solid phase—in the case of juglone and plumbagin. The area of band near 1237 cm −1 (1100–1400 cm −1 ) is in the spectrum of a very rich DNA.…”

Molecular Dynamics Study of the Hybridization between RNA and Modified Oligonucleotides

“…Molecular modeling techniques, in particular molecular dynamics (MD) simulations, have been valuable tools for understanding the energetic and structural properties of modified nucleic acids since the early years of their discovery. − The effects of sequence and chirality on PS-modified oligonucleotides (ONs) were analyzed through simulations. ,− The destabilization of the PS-DNA/DNA duplex by R-isomer PS (abbreviated Rp, and similarly for Sp) was explained by the stiffness of the backbone and the steric repulsion between the sulfur atom and the C–H group of sugar. , Rp and Sp were also shown to have the opposite effects on minor groove width . The conformation and solvation of LNA were analyzed and compared with those of DNA and RNA. − LNA induced C3′-endo conformation of its complementary DNA strand, indicating its strong preference for A-form conformation .…”

Phosphodiester backbone of the CpG motif within immunostimulatory oligodeoxynucleotides augments activation of Toll-like receptor 9

“…Therefore, this conserved type of modification has been rapidly accepted in therapeutic applications due to the markedly enhanced immunostimulatory power 21 . However, the replacement of nonbridging oxygen by a sulfur atom changes the physical and chemical properties of the phosphate bond: increased Van der Waals radius (1.85 Å P = S vs. 1.44 Å P = O) with lengthening of the P-S bond (2.0 Å P = S vs. 1.5 Å P = O) and a changed partial charge distribution of the phosphate moiety 25 , 26 . This replacement also creates a chiral center (“Sp” or “Rp” conformation) at each phosphate bond, which generates multiple isomers of the oligo.…”

“…However, the ODNs with PD-based 5′-TCG (first CpG motif) effectively activated the hTLR9 mutants, indicating that phosphate bond chemistry significantly effects the binding of the unmethylated CpG motif to TLR9. We propose that smaller sized PD bond and partial charge distribution leading to a more positive phosphate atom and an overall increase in the negative charge density of other oxygen atoms 26 will make the interaction of a CpG dinucleotide with aa residues of the CpG binding pocket stronger and therefore less sensitive to point mutations within TLR9. It is difficult to completely exclude the impact of PTO bond chirality on the CpG motif– TLR9 binding mechanism, although it is interesting that a change as small as the replacement of a PTO linkage of a single CpG motif with a PD linkage of a single CpG motif significantly improves the activation potency of PTO-based ODNs.…”