Effects of the central potassium ions on the G-quadruplex and stabilizer binding.

Human telomeres undertake the structure of intra-molecular parallel G-quadruplex in the presence of K in eukaryotic cell. Stabilization of the telomere G-quadruplex represents a potential strategy to prevent telomere lengthening by telomerase in cancer therapy. Current work demonstrates that the binding of central K with the parallel G-quadruplex is a coordinated water directed step-wise process. The K above the top G-tetrad is prone to leak into environment and the 5'-adenine quickly flips over the top G-tetrad, leading to the bottom gate of G-tetrads as the only viable pathway of K binding. Present molecular dynamics studies on the two most potent stabilizers RHPS4 and BRACO-19 reveal that the central K has little influence on the binding conformations of the bound stabilizers. But without the central K, either RHPS4 or BRACO-19 cannot stabilize the structure of G-quadruplex. The binding strength of stabilizers evaluated by the MM-PBSA method follows the order of BRACO-19> RHPS4, which agrees with the experimental results. The difference in binding affinities between RHPS4 and BRACO-19 is probably related to the ability to form intramolecular hydrogen bonds and favorable van del Waals interactions with G-quadruplex. In the models that have one central K located at the upper/lower binding site, the corresponding top/bottom stacked stabilizers show more favorable binding affinities, indicating the apparent promoting effect of central K on the stabilizer binding. Our findings provide further insights into the regulatory effect of K on the G-quadruplex targeted binding, which is meaningful to the development of G-quadruplex stabilizers.