Destabilizing Interactions in human telomeric G-quadruplex multimers

G-Quadruplexes are secondary structures that may form in G-rich nucleic acid sequences. The extended overhang at the ends of human telomeres has the potential to form multiple G-Quadruplexes that are crucial in regulating key biological processes. Here, we employ small-angle X-ray scattering-guided extremely coarse-grained simulations to provide a picture of the arrangement of G-Quadruplexes in long telomeric sequences. We observe significant destabilizing interactions between G-Quadruplexes, thus making the stacked conformation less prevalent. A helix-coil model is proposed to analytically describe the stacking-unstacking equilibrium within G-Quadruplex multimers and predict the occurrence of stacked and unstacked G-Quadruplex multiplets in arbitrarily long sequences. © 2025 The Authors. Published by American Chemical Society.