Origin of Ion Specificity of Telomeric DNA G-Quadruplexes Investigated by Free-Energy Simulations

Telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) that form G-quadruplex structures made of stacked guanines with monovalent cations bound at a central cavity. Although different ions can stabilize a G-quadruplex structure, the preferred bound ions are typically K or Na. Several different strand-folding topologies have been reported for Q-quadruplexes formed from telomeric repeats depending on DNA length and ion solution condition. This suggests a possible dependence of the ion selectivity of the central pore on the folding topology of the quadruplex. Molecular dynamics free energy perturbation has been employed to systematically study the relative affinity of the central quadruplex pore for different cation types and the associated energetic and solvation contributions to ion selectivity. The calculations have been performed on two different common quadruplex folding topologies. For both topologies, the same ion selectivity was found with a preference for K followed by Rb and Na, which agrees with the experimentally determined preference for most investigated quadruplexes. The selectivity is determined by a balance between attractive Coulomb interactions and loss of hydration but also modulated by van der Waals contributions. Specificity is mediated by the central guanines and no significant contribution of the nucleic acid backbone. The simulations indicate that different topologies might be stabilized by ions bound at the surface or alternative sites of the quadruplex because the ion specificity of the central pore does not depend on the strand folding topology.