The structure of parallel-stranded duplexes of DNA-containing a mixture of guanines (G) and adenines (A) is studied by means of molecular dynamics (MD) simulation, as well as NMR and circular dichroism (CD) spectroscopy. Results demonstrate that the structure is based on the Hoogsteen motif rather than on the reverse Watson-Crick one. Molecular dynamics coupled to thermodynamic integration (MD/TI) calculations and melting experiments allowed us to determine the effect of 8-amino derivatives of A and G and of 8-amino-2'-deoxyinosine on the stability of parallel-stranded duplexes. The large stabilization of the parallel-stranded helix upon 8-amino substitution agrees with a Hoogsteen pairing, confirming MD, NMR, and CD data, and suggests new methods to obtain DNA triplexes for antigene and antisense purposes.