Abstract
The alkali metal ion affinity of guanine quadruplexes has been studied using dispersion-corrected density functional theory (DFT-D). We have done computational investigations in aqueous solution that mimics artificial supramolecular conditions where guanine bases assemble into stacked quartets as well as biological environments in which telomeric quadruplexes are formed. In both cases, an alkali metal cation is needed to assist self-assembly. Our quantum chemical computations on these supramolecular systems are able to reproduce the experimental order of affinity of the guanine quadruplexes for the cations Li(+), Na(+), K(+), Rb(+), and Cs(+). The strongest binding is computed between the potassium cation and the quadruplex as it occurs in nature. The desolvation and the size of alkali metal cations are thought to be responsible for the order of affinity. Until now, the relative importance of these two factors has remained unclear and debated. By assessing the quantum chemical 'size' of the cation, determining the amount of deformation of the quadruplex needed to accommodate the cation and through the energy decomposition analysis (EDA) of the interaction energy between the cation and the guanines, we reveal that the desolvation and size of the alkali metal cation are both almost equally responsible for the order of affinity.
Highlights
Guanine-rich sequences of DNA, which occur at crucial regulatory hotspots of the human genome, such as telomeres, promoters and immunoglobulin switch regions, can fold into a non-duplex four-stranded type of structure.[1]
We showed that alkali metal cations located in the central channel of guanine quadruplexes (GQs) weaken the hydrogen bonds, the synergy still persists in telomere-like structures
We show that the Gibbs free energy of solvation and the ionic radius of the alkali metal cation are both of almost equal importance for the order of affinity for the cavity in the guanine quadruplexes
Summary
Guanine-rich sequences of DNA, which occur at crucial regulatory hotspots of the human genome, such as telomeres, promoters and immunoglobulin switch regions, can fold into a non-duplex four-stranded type of structure (see Fig. 1).[1]. The general idea on the role of the alkali metal cation is that by being located between two quartets, it generates cation– dipole interactions with eight guanines.[6] In that way, it is thought to reduce the repulsion of the eight central oxygen atoms, enhance the hydrogen bond strength and stabilize quartet stacking. This has been rationalized by looking at the electrostatic potential map of a G-tetrad which shows a significant concentration of negative charge in the central area of the G-tetrad.6c Another theoretical work has investigated the cation–quadruplex interaction and revealed polarization of charge towards the cation.[7]
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