期刊
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
卷 42, 期 9, 页码 902-909出版社
WILEY
DOI: 10.1111/1440-1681.12443
关键词
binding process; molecular dynamics; principal component analysis; molecular mechanic Poisson-Boltzmann surface area; density functional theory
资金
- National Basic Research Program of China [2012CB911200, 2012CB911204]
- National Natural Science Foundation of China [31100584]
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 about 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 centre 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.
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