Nucleic
Acid Quadruplexes Based on 8‑Halo-9-deazaxanthines:
Energetics and Noncovalent Interactions in Quadruplex Stems
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Abstract
Structural and energetic features
of artificial DNA quadruplexes
consisting of base tetrads and their stacks with Na<sup>+</sup>/K<sup>+</sup> 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<sup>+</sup> induces larger electron
polarization from the quadruplex toward the ion, whereas K<sup>+</sup> 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