Effect of the chemical environment of the DNA guanine quadruplex on the free energy of binding of Na and K ions.

Guanine quadruplex (G-quadruplex) structures play a vital role in stabilizing the DNA genome and in protecting healthy cells from transforming into cancer cells. The structural stability of G-quadruplexes is greatly enhanced by the binding of monovalent cations such as Na+ or K+ into the interior axial channel. We computationally study the free energy of binding of Na+ and K+ ions to two intramolecular G-quadruplexes that differ considerably in their degree of rigidity and the presence or absence of terminal nucleotides. The goal of our study is two-fold. On the one hand, we study the free energy of binding every ion, which complements the experimental findings that report the average free energy for replacing Na+ with K+ ions. On the other hand, we examine the role of the G-quadruplex structure in the binding free energy. In the study, we employ all-atom molecular dynamics simulations and the alchemical transformation method for the computation of the free energies. To compare the cation-dependent contribution to the structural stability of G-quadruplexes, we use a two-step approach to calculate the individual free energy difference Δ G of binding two Na+ and two K+ to two G-quadruplexes: the unimolecular DNA d[T2 GT2 (G3 T)3 ] (Protein Data Bank ID 2M4P) and the human telomeric DNA d[AGGG(TTAGGG)3 ] (PDB ID 1KF1). In contrast to the experimental studies that estimate the average free energy of binding, we find a varying difference of approximately 2-9 kcal/mol between the free energy contribution of binding the first and second cation, Na+ or K+ . Furthermore, we found that the free energy of binding K+ is not affected by the chemical nature of the two quadruplexes. By contrast, Na+ showed dependency on the G-quadruplex structure; the relatively small size allows Na+ to explore larger configurational space than K+ . Numerical results presented here may offer reference values for future design of cationic drug-like ligands that replace the metal ions in G-quadruplexes.