title: Effects of the central potassium ions on the G-quadruplex and stabilizer binding.
abstract: 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.
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China. Electronic address: zhgwang@aliyun.com.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province 311121, China; Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Vitoria 3004, Australia; Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia. Electronic address: junping.liu@monash.edu.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
mesh_terms: D000166:Acridines / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000494:pharmacology*; D025341:Principal Component Analysis; D016615:Telomere / Q000737:chemistry; D013816:Thermodynamics
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D007477:Ions; D011188:Potassium; C454064:BRACO-19
keywords: Binding free energy; Binding process; G-Quadruplex; Potassium ion