Abstract: We used molecular dynamics simulations to investigate the structure and stability of a mixed-type hybrid guanine-quadruplex complex in human telomere. The effects of coordinated K+ ions, drug ligands (TMS) and solvent molecules on stability are discussed. Our results show that coordination between K+ ions and O6 in guanine bases decreases the electrostatic repulsion of the diagonal O6-O6. As a result, planar G-tetrads are stabilized by Hoogsteen hydrogen bonds that are formed by four neighboring guanine bases. On the other hand, stacking interactions between G-tetrads as well as the G-tetrad and the drug ligand lower the total energy of the G-quadruplex complex and thus stabilize it. In addition, water molecules are mainly located around TTA loops, the backbone and sugar rings which result in larger root mean square deviations (RMSDs) compared with other G-quadruplex fragments. However, since water does not enter the G-quadruplex complex cages during the 3 ns simulation, the influence of solvent on the stability of the G-tetrads is insignificant.

Key words: G-quadruplex, G-tetrad, Hoogsteen hydrogen bond, π-&pi, stacking interaction, Molecular dynamics simulation, Telomestatin