Importance of model size in quantum mechanical studies of DNA intercalation.

The convergence of DFT-computed interaction energies with increasing binding site model size was assessed. The data show that while accurate intercalator interaction energies can be derived from binding site models featuring only the flanking nucleotides for uncharged intercalators that bind parallel to the DNA base pairs, errors remain significant even when including distant nucleotides for intercalators that are charged, exhibit groove-binding tails that engage in noncovalent interactions with distant nucleotides, or that bind perpendicular to the DNA base pairs. Consequently, binding site models that include at least three adjacent nucleotides are required to consistently predict converged binding energies. The computationally inexpensive HF-3c method is shown to provide reliable interaction energies and can be routinely applied to such large models.

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.