MD Simulations and CD Spectroscopies of (Benz)Acridine: rDNA G-Quadruplex Complexes

Abstract

In both prokaryotic and eukaryotic cells, guanine-rich stretches of DNA sequences are found in gene regulatory regions and telomeric DNAs to form G-quadruplexes, and they are involved in many fundamental biological processes and have been implicated in a number of diseases including cancer. While most previous G-quadruplex studies have focused on telomeric G-quadruplexes for validating targets for anticancer therapy, the nucleolar G-quadruplexes may be an even more promising target for chemotherapeutic intervention. The nucleolus plays a central role in tumor pathology because it controls the high level of ribosomal RNA (rRNA) synthesis necessary to sustain ribosome biogenesis during rapid cancer cell growth. Ribosome biogenesis occurs in the nucleolus and is tightly regulated by many cell signaling pathways that converge on the RNA polymerase I complex (Pol I). Using small molecules (drugs) to disrupt ribosome biogenesis represents an attractive strategy for selectively killing cancer cells. Aromatic acridines that sit on top of a G-quadruplex tetrad via π-π stacking interactions have been extensively explored as scaffolds for developing G-quadruplex-specific binders. In this present study, we performed MD simulations of 13 modeled putative rDNA G-quadruplexes that have been characterized via CD spectra to form G-quadruplexes. In addition, we simulated their interactions with designed acridines and benzacridines and analyzed them using a set of novel order parameters to quantify their binding selectivities. We are currently validating our computational predictions via CD spectra. In one G-quadruplex we studied, NUC 23, CD spectra shows that it adopts a parallel topology structure that is further stabilized upon interactions with benzacridine. In excellent agreement, we also observe the same phenomenon in our MD simulations.