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Sequence effects on energetic and structural properties of phosphorothioate DNA: a molecular modelling study
B Hartmann1, H Bertrand, S Fermandjian
1Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, UPR CNRS 9080, 13 rue Pierre et Marie Curie, 75005 Paris, France.
Nucleic Acids Research
|August 24, 1999
Summary
Phosphorothioate (PS) oligonucleotides, used in new drugs, alter DNA stability and structure. Molecular modeling shows PS group effects are local and additive, aiding prediction of DNA behavior.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Molecular Biology
Background:
- Phosphorothioate (PS) oligonucleotides are a novel drug class.
- They feature a sulfur atom replacing an oxygen in the phosphodiester backbone.
- This modification introduces chirality at the phosphorus atom, affecting DNA properties.
Purpose of the Study:
- To assess the energetic, structural, and biological impacts of phosphorothioate modifications in DNA.
- To investigate the influence of chirality (PSS or PSR) on DNA behavior.
- To understand sequence-specific effects on PS oligonucleotide stability.
Main Methods:
- Molecular mechanics calculations were employed.
- Regular DNA sequences (d(YR)8.d(YR)8 and d(RR)8.d(YY)8) were analyzed.
- Energetic properties, including electrostatic and van der Waals terms, were evaluated.
Main Results:
- Both PS(R) and PSS oligomers showed destabilization, primarily due to electrostatic changes.
- Chirality introduced additional energetic effects, more pronounced in PSS than PSR oligomers.
- Sequence context, especially the preceding base, significantly impacted stability without major conformational changes.
Conclusions:
- PS modifications alter DNA stability and energetics but not significantly its conformation.
- Sequence effects on PS oligonucleotide energetics are local and additive.
- Studying modified dinucleotide steps can predict the behavior of double-stranded PS-DNA.