Charge–dipole interactions in G-quadruplex thrombin-binding aptamer

DNAs form various structures through hydrogen-bonding, base-stacking and electrostatic interactions. Although these noncovalent interactions are known to be cooperative in stabilizing a G-quadruplex (G4) structure of DNA, we find from all-atom molecular dynamics simulations that the electrostatic charge–dipole interaction is competitive with both hydrogen-bonding and base-stacking interactions. For the thrombin-binding aptamer (TBA) forming a chair-type antiparallel G4 structure, we have examined effects of an intercalating metal ion [K⁺, Sr²⁺, Mⁿ⁺: an ion having a charge of n⁺ (n = 1–4) with the ionic radius of K⁺] on structural properties and noncovalent interactions. When K⁺ in the TBA·K⁺ complex is replaced with Sr²⁺, guanine dipoles in the two G-tetrads are realigned toward the central metal ion, thereby distorting the planar G4 geometry. Replacing K⁺ with Sr²⁺ significantly enhances the charge–dipole interaction but substantially reduces the number of hydrogen bonds in the G-tetrads. In the case of TBA·Mⁿ⁺ complexes, as the charge n increases, the charge–dipole interaction increases but both of the hydrogen-bonding and base-stacking interactions decrease. These results suggest that the charge–dipole interaction realigning guanine dipoles in the G-tetrads is not cooperative but competitive with both hydrogen-bonding and base-stacking interactions favoring the planar G-tetrad geometry. Obviously, the charge state of an intercalating metal ion is as important as the ionic radius in forming a stable G4 structure. Thus, a delicate balance between these competing noncovalent interactions makes the chair-type antiparallel G4 structure of TBA selective for intercalating metal ions.