G-quadruplexes (G4s) are noncanonical nucleic acid structures especially abundant in telomeres, where they can assemble into higher-order multimers. Stabilization of these assemblies is recognized as a promising strategy for suppressing tumor proliferation. Elucidating their structural stability and topological responses to small-molecule binding is therefore essential for advancing their therapeutic potential. Here, we employ a multi-technique approach, combining circular dichroism and small-angle X-ray scattering with extremely coarse-grained simulations, to characterize the impact of four well-established ligands on telomeric G4 dimers. All ligands promote significant stacking interactions between the G4 units in the dimer, leading to more compact complexes, with the fraction of stacked units exhibiting a linear dependence on the effective distance between their centers of mass. Nonetheless, each ligand predominantly interacts with a single G4 unit at a time, inducing thermal stabilization of the monomers within the dimer comparable to that of the corresponding monomeric species. Strikingly, the extent of ligand-induced topological rearrangements observed in the complexes is associated with their stability, but not with compactness. These results provide new insights into ligand interactions with G4 dimers and offer mechanistic guidance for the design of G4 multimer stabilizers.
Bertini et al. (Thu,) studied this question.