Parameterization and Simulation of the Physical Properties of Phosphorothioate Nucleic Acids

The physical properties of nucleic acid complexes containing phosphorothioate backbone modifications are studied using molecular mechanics and dynamics calculations. Parameters for the phosphorothioate oligonucleotide are derived from ab initio calculations in a manner consistent with the AMBER 4.1 force field database. The force field is applied to simulate the structural properties of hybrid DNA:RNA duplexes starting in both the A- and B-form geometries. The results show the phosphorothioate-DNA:RNA complex has an overall A-form geometry with minor groove widths between A- and B-form. Although model compound calculations indicate the sulfur substitution increases torsional flexibility around the phosphorous, molecular dynamics simulations show the modification does not have a great effect on backbone geometry. The results are also compared with previous studies of standard DNA:RNA hybrid structures. While a wide range of sugar puckers are typically associated with the DNA strand of hybrid duplexes, the average structures reported here show C3′-endo puckering, suggesting phosphorothioate substitutions may influence sugar conformation.