title: Characterization of potassium binding with human telomeres.
abstract: 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.
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.|Department of Immunology, Central Clinical School, Monash University, Melbourne, Vic., Australia.|Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
keywords: binding process; density functional theory; molecular dynamics; molecular mechanic Poisson-Boltzmann surface area; principal component analysis