Conformational Plasticity of Parallel G-Quadruplex─Implications on Duplex-Quadruplex Motifs

DNA G-quadruplexes are essential motifs in molecular biology performing a wide range of functions enabled by their unique and diverse structures. In this study, we focus on the conformational plasticity of the most abundant and biologically relevant parallel G-quadruplex topology. A multipronged approach of structure survey, solution-state NMR spectroscopy, and molecular dynamics simulations unravels subtle yet essential features of the parallel G-quadruplex topology. Stark differences in flexibility are observed for the nucleotides depending upon their positioning in the tetrad planes that are intricately correlated with the conformational sampling of the propeller loop. Importantly, the terminal nucleotides in the 5'-end versus the 3'-end of the parallel quadruplex display differential dynamics that manifests their ability to accommodate a duplex on either end of the G-quadruplex. The conformational plasticity characterized in this study provides essential cues toward biomolecular processes such as small molecular binding, intermolecular quadruplex stacking, and implications on how a duplex influences the structure of a neighboring quadruplex.