The binding model of adenosine-specific DNA aptamer: Umbrella sampling study.

We report a novel model of the selective binding mechanism of adenosine-specific DNA aptamer. Our theoretical investigations of AMP (Adenosine monophosphate) dissociation from aptamer-AMP complexes reveals new details of aptamer molecular specificity and stabilisation factors. Umbrella sampling MD calculations using parmbsc1 force field shows that the disordered structure of the internal loop of the unbound aptamer hairpin has a characteristic packing of guanines, which prevents barrier-free penetration of ligands into the site cavity. Also, this disordered structure of the unbound aptamer has a network of hydrogen bonds stabilising the cavity near the target guanines within the binding sites during the whole binding process. We suggested that the first AMP molecule binds to the disordered structure of the site closest to the aptamer hairpin stem and spends some free energy on ordering of the internal loop. Then the second AMP molecule binds to the ordered site closest to the aptamer hairpin loop with a lower energy gain. As a result, the induced-fit binding model is the most applicable for this aptamer and does not contradict the modern experimental NMR and calorimetry data.