Nucleic Acid Quadruplexes Based on 8-Halo-9-deazaxanthines: Energetics and Noncovalent Interactions in Quadruplex Stems

Structural and energetic features of artificial DNA quadruplexes consisting of base tetrads and their stacks with Na+/K+ ion(s) inside the central pore and incorporating halogenated derivatives of xanthine, 8-fluoro-9-deazaxanthine (FdaX), 8-chloro-9-deazaxanthine (CldaX), 8-bromo-9-deazaxanthine (BrdaX), or 8-iodo-9-deazaxanthine (IdaX), have been investigated by modern state-of-the-art computational tools. The DNA (or RNA) quadruplex models based on 8-halo-9-deazaxanthines are predicted to be more stable relative to those with unmodified xanthine due to the increased stabilizing contributions coming from all three main types of weak interactions (H-bonding, stacking, and ion coordination). Methods for analyzing the electron density are used to understand the nature of forces determining the stability of the system and to gain a predictive potential. Quadruplex systems incorporating polarizable halogen atoms (chlorine, bromine, or iodine) benefit significantly from the stabilizing stacking between the individual tetrads due to an increased dispersion contribution as compared to xanthine and guanine, natural references used. Ion coordination induces a significant rearrangement of electron density in the quadruplex stem as visualized by electron deformation density (EDD) and analyzed by ETS-NOCV and Voronoi charges. Na+ induces larger electron polarization from the quadruplex toward the ion, whereas K+ has a higher propensity to electron sharing (identified by QTAIM delocalization index). We expect that our results will contribute to the development of novel strategies to further modify and analyze the natural G-quadruplex core.