Sensing diclofenac with DNA aptamers: an atomistic picture from molecular modelling

Sensors with responsive components based on short nucleic acid chains called aptamers have emerged as promising devices for the environmental detection of pollutants, offering a cheaper and easily implementable alternative to more classical analytical techniques. However, a molecular-level picture of the mechanisms responsible for these sensors' sensitivity and specificity is still lacking. With the aim of filling this gap we present the results of a combined docking and classical molecular dynamics approach on an aptamer engineered to target diclofenac (DCF), and recently tested for DCF detection in experimental electrochemical devices. On top of the setup of the computational approach enabling the study of these complex systems, our results point out the key role played by hairpin loops regions as an environment favoring binding due to their balance between structure and mobility that allows them to adapt to the ligands. Molecular dynamics simulations reveal the origin of the peculiar specificity for DCF to likely be an intense interaction with a triplet of consecutive nucleotides driven essentially by attractive dispersion forces acting between the aromatic rings of DCF and the nucleoside aromatic groups, an interaction that is not established in the case of another competing molecule, paracetamol. Overall, our results suggest that the sensitivity of aptamers is crucially associated with their folding substructure and points at how the atomistic picture provides interesting and effective tools for their optimization.