In conclusion, we used a fuel-driven reaction cycle to alter the likelihood of folding of a DNA hairpin. The reaction cycle operates directly on the DNA sequence, i.e., it acts on a modified thymine bearing two negatively charged carboxylic acids that become neutral and more rigid, which decreases its steric hindrance, electrostatic repulsion, and increases its ability to base stack upon folding. Future single-molecule studies should further elucidate the kinetics of folding and unfolding of this system, giving a complete picture of the energy landscape. Further changes in the molecular design will increase the energy difference between the active and precursor state even further.