Re-examination of the intrinsic, dynamic and hydration properties of phosphoramidate DNA

Intrinsic energetic and solvation factors contributing to the unusual struc tural and biochemical properties of N3'-phosphoramidate DNA analogs have be en re-examined using a combination of quantum mechanical and molecular dyna mics methods. Evaluation of the impact of the N3'-H substitution was perfor med via comparison of NT-phosphoramidate DNA starting from both A- and B-fo rm structures, B-form DNA and A-form RNA. The N3'-H group is shown to be fl exible, undergoing reversible inversion transitions associated with motion of the hydrogen atom attached to the N3' atom. The inversion process is cor related with both sugar pucker characteristics as well as other local backb one torsional dynamics, yielding increased dihedral flexibility over DNA. S olvation of N3'-phosphoramidate DNA is shown to be similar to RNA, consiste nt with thermodynamic data on the two species. A previously unobserved intr insic conformational perturbation caused by the N5'-phosphoramidate substit ution is identified and suggested to be linked to the differences in the pr operties of N3'- and N5'-phosphoramidate oligonucleotide analogs.