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

Abstract

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.

Understanding the Origin of 2D Self-Assembly of Tricarbazole Macrocycles: An Integrated Quantum Mechanical/Molecular Dynamics Study

“…An important way to address these issues is by using advanced computational methods. These methods can play an important role in elucidating the structure–property relationships in such self-assembled systems, where electronic structure theory employing quantum mechanical (QM) treatments provides insights into the (static) fundamental properties of interacting molecular systems. − Another complementary computational tool, molecular dynamics (MD) simulations, offers detailed exploration of the dynamical behavior of self-assembling systems at different time scales . In particular, computational studies have provided valuable insights into various self-assembly mechanisms, as reviewed recently. − QM and MD can be used either independently or often in conjunction with experimental techniques for obtaining qualitative and quantitative insights toward various supramolecular architectures. , …”

Systematic Study of Heteroarene Stacking Using a Congeneric Set of Molecular Glues for Procaspase-6

“…Such analyses are necessarily qualitative in nature, however, since interaction energies cannot be extracted from the purely structural information. Various computational studies have provided additional insight, from the early work of Hunter and Sanders to more recent studies exploring substituent effects − and the effects of introducing heteroatoms − (i.e., heteroarene–aryl stacking). Most recently, Wheeler and co-workers have introduced heterocycle descriptors derived from computed molecular electrostatic potentials (ESPs) that enable predictions of the maximum strength of diverse heteroarene stacking interactions without costly ab initio computations. − …”

“…Most recently, Wheeler and co-workers have introduced heterocycle descriptors derived from computed molecular electrostatic potentials (ESPs) that enable predictions of the maximum strength of diverse heteroarene stacking interactions without costly ab initio computations. 15 − 18 …”

A Comprehensive Empirical–Computational Study of Diverse Het-eroarene Stacking under Physiological Conditions

“…Of course, such analyses are necessarily qualitative in nature, since interaction energies cannot be extracted from the purely structural information. Providing considerable insight into the nature of stacking interactions have been various computational studies, from the early work of Hunter and Sanders 4 , to more recent studies exploring substituent effects [5][6][7][8][9] and the effects of introducing heteroatoms into the arene [10][11][12][13][14][15][16] (i.e., heteroarene-aryl stacking). Most recently, Wheeler and co-workers have introduced heterocycle descriptors derived from computed molecular electrostatic potentials (ESPs) that enable predictions of diverse heteroarene stacking interactions without costly ab initio computations.…”

“…Most recently, Wheeler and co-workers have introduced heterocycle descriptors derived from computed molecular electrostatic potentials (ESPs) that enable predictions of diverse heteroarene stacking interactions without costly ab initio computations. [15][16][17][18] Among experimental model systems used to study heteroarene-aryl stacking are synthetic host-guest systems 19 and molecular "torsion balances". [20][21][22] Applications of the latter to heteroarene stacking include Shimizu's cleft-like N-aryl imides, 23 Gung's triptycenes, 24 and Gellman's tertiary amide foldamers 25 (Figure 1).…”