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Human telomeres are G-rich tandem repeats that assume G-quadruplex structures at the ends of chromosomes. Stabilization of telomeric G-quadruplex represents a significant drug target for inhibiting the telomerase activity that is required in ~85% of cancers. Metal ions have been revealed as important stabilizers to DNA G-quadruplexes, but their binding process with human telomeric G-quadruplex remains unclear. In this report, we show that K(+) traverses into the G-tetrads center of two G-tetrad layers through the half-capped top pathway constructed by the two edge-wise loop bases. The binding is mediated by the electrostatic interactions between K(+) and the nearby bases of G-tetrads. However, direct traverse of K(+) into the interior of G-quadruplex is negatively regulated by the steric hindrance of water molecules. Once K(+) enters the G-quadruplex, stabilization of the in-plane or sandwiched conformation of the telomeric G-quadruplex-K(+) complex is maintained by surrounding water molecules. These findings provide insights into the atomic interactions between K(+) and telomere G-tetrads for targeted drug design. This article is protected by copyright. All rights reserved.