Connecting Structure, Conformation and Energetics of Human Telomere G-quadruplex Multimers

Abstract

G-quadruplexes (G4s) are helical four-stranded structures forming from guanine-rich nucleic acid sequences, which are thought to play a role in cancer development and malignant transformation. Most current studies focus on G4 monomers, yet under suitable and biologically relevant conditions G4s undergo multimerization. Here, we address the structural, conformational and energetic features of G4 multimers formed in solutions by the human telomere sequence. A novel multi-technique approach is used combining Small Angle X-ray Scattering (SAXS) and circular dichroism experiments with coarse-grained simulations, to provide quantitative information about large-scale structural features and the stability of G4 multimers. The latter show a significant polydispersity with an exponential distribution of contour lengths, suggesting a step-growth polymerization. On increasing DNA concentration, the strength of G4 stacking interaction increases, as well as the number of the units in the aggregates, with dimers and trimers as the most probable forms. At the same time, a variation of G4 conformation is observed. Our findings provide a quantitative picture of human telomere G4 multimers, which must be accounted for to achieve a rational design of anticancer drugs targeting DNA structures.