Characterization of the Monovalent Ion Position and Hydrogen-Bond Network in Guanine Quartets by DFT Calculations of NMR Parameters

Conformational stability of G‐quartets found in telomeric DNA quadruplex structures requires the coordination of monovalent ions. Here, an extensive Hartree–Fock and density functional theory analysis of the energetically favored position of Li+, Na+, and K+ ions is presented. The calculations show that at quartet–quartet distances observed in DNA quadruplex structures (3.3 Å), the Li+ and Na+ ions favor positions of 0.55 and 0.95 Å outside the plane of the G‐quartet, respectively. The larger K+ ion prefers a central position between successive G‐quartets. The energy barrier separating the minima in the quartet‐ion‐quartet model are much smaller for the Li+ and Na+ ions compared with the K+ ion; this suggests that K+ ions will not move as freely through the central channel of the DNA quadruplex. Spin–spin coupling constants and isotropic chemical shifts in G‐quartets extracted from crystal structures of K+‐ and Na+‐coordinated DNA quadruplexes were calculated with B3LYP/6‐311G(d). The results show that the sizes of the trans‐hydrogen‐bond couplings are influenced primarily by the hydrogen bond geometry and only slightly by the presence of the ion. The calculations show that the RN2N7 distance of the N2‐H2⋅⋅⋅N7 hydrogen bond is characterized by strong correlations to both the chemical shifts of the donor group atoms and the h2JN2N7 couplings. In contrast, weaker correlations between the h3JN1C6′ couplings and single geometric factors related to the N1‐H1⋅⋅⋅O6C6 hydrogen bond are observed. As such, deriving geometric information on the hydrogen bond through the use of trans‐hydrogen‐bond couplings and chemical shifts is more complex for the N1‐H1⋅⋅⋅O6C6 hydrogen bond than for the N2‐H2⋅⋅⋅N7 moiety. The computed trans‐hydrogen‐bond couplings are shown to correlate with the experimentally determined couplings. However, the experimental values do not show such strong geometric dependencies. Electronic structure calculations on DNA quadruplex model systems predict that Na+ and Li+ prefer positions just outside one of the G‐quartets in the quadruplex, whereas K+ prefers a position between two successively stacked G‐quartets. Density functional theory calculations of the NMR trans‐hydrogen‐bond coupling constants show a much stronger correlation between the coupling constants and hydrogen‐bond geometry for the N‐H⋅⋅⋅N hydrogen bond compared with the N‐H⋅⋅⋅CO hydrogen bond in G‐quartets.