The Investigation Of The Quadruplex DNA-Drug Binding Process

Single stranded guanine rich DNA sequences can associate strongly together, either inter-or intra-molecularly, to form a variety of four-stranded quadruplex structures, all containing stacked guanine-tetrads, as revealed in several crystal and NMR ex-periments, called G-quadruplex DNA. This structure is generated through the as-sociation of four guanines bound through Hoogsteen base pairing and stable under near-physiological conditions.Computational analysis revealed the prevalence of G-quadruplex DNA in key regulatory regions of the human genome, such as promoters, gene bodies and un-translated region. G-quadruplex DNA were also present at the ends of chromo-somes, telomeres, although it occupy low ratio (25%) indicated by the recent re-search of Balasubramanian.Interest in G-quadruplex DNA has been increased by the discovery that stabi-lized quadruplex structures negatively affect enzyme-catalyzed elongation of telom-eric sequences in vitro. It has been shown that ligands that interact with quadru-plexes can act as inhibitors of the enzyme telomerase, whose function is to pro-tect tumor cells against telomere loss during replication. Given that up to85%of all cancers rely on the activity of telomerase for continued growth, control of telomerase-mediated telomere elongation through G4DNA recognition is perceived as having therapeutic potential.The widely used drugs to recognize and interact with cancer cell DNA are anthra-cyclines daunomycin and doxorubicin. They are now in market as chemotherapy agents. This kind of drugs consist of an anthraquinone ring and an amino sugar group and the anti-cancer activity of these drugs is due to their intercalation into DNA which may disrupt replication and transcription of genomic DNA and lead to the death of cancer cell.In2003, Clark and his team reported the first crystal structure determination of a parallel G-quadruplex DNA (formed from four molecule of d(TGGGGT)) and daunomycin complex. They found that a set three daunomycin molecules is stacked onto the5’end of the quadruplex where they make weak pi-pi interactions with guanimes in the terminal tetrad. This experiment revealed the first and importance binding mode been token place on quadruplex DNA recognition:end binding mode, but there has been wonder whether it is the only way of recognition could happen on Gquadruplex DNA. Moreover, the binding process and reaction details still remain elusive.To probe this information, we performed all-atom molecular (a G4DNA motif and four daunomycin molecules) dynamics simulations with explicit water, starting from an unbound state. From the simulation trajectories, we observed new binding modes besides end-stacking mode reported by Clark, named groove binding mode. To verify the stability of these binding modes and eliminate the influence on each other, we have another100ns simulations about each binding modes which contain one G4DNA fragment and one drug.This paper is organized as follow. In Sec. II, we introduced the setup of our simulation systems and parameters for characterizing DNA and complex. In Sec. Ⅲ we analyzed the trajectories and get several binding modes. In Sec. Ⅳ, we conclude and discuss the purpose of our results.