Intrinsic energetic and solvation factors contributing to the unusual structural and biochemical properties of N3'-phosphoramidate DNA analogs have been re-examined using a combination of quantum mechanical and molecular dynamics methods. Evaluation of the impact of the N3'-H substitution was performed via comparison of N3'-phosphoramidate DNA starting from both A- and B-form structures, B-form DNA and A-form RNA. The N3'-H group is shown to be flexible, undergoing reversible inversion transitions associated with motion of the hydrogen atom attached to the N3' atom. The inversion process is correlated with both sugar pucker characteristics as well as other local backbone torsional dynamics, yielding increased dihedral flexibility over DNA. Solvation of N3'-phosphoramidate DNA is shown to be similar to RNA, consistent with thermodynamic data on the two species. A previously unobserved intrinsic conformational perturbation caused by the N5'-phosphoramidate substitution is identified and suggested to be linked to the differences in the properties of N3'- and N5'-phosphoramidate oligonucleotide analogs.
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