Better Sensing through Stacking: The Role of Non-Covalent Interactions in Guanine-Binding Sensors

A series of aryl-substituted naphthyridine-based sensors for 9-alkylguanine was analyzed using density functional theory and correlated ab initio methods. First, the 2-acetamido-1,8-naphthyridine backbone of these sensors was examined with rigorous ab initio methods and was shown to exhibit a guanine-binding energy commensurate with that of cytosine. Second, computational analyses of a guanine-specific fluorescent sensor from Fang and co-workers ( Org. Lett. 2016, 18, 1724) resulted in a revised binding model and showed that π-stacking interactions with a pendant pyrenyl group are vital for strong guanine binding. Finally, 24 related guanine sensors with varying aryl groups were studied. Overall, it was found that both the geometry and the point of attachment of the pendant aryl groups significantly impact the guanine-binding affinity. This occurs through both the direct modulation of the π-stacking interactions with guanine and the secondary geometric effects that influence the strength and number of hydrogen bonds between guanine and the ethylenediamine linker connecting the arene to the naphthyridine backbone.