LAUSR

It is increasingly recognised that the structure and dynamics of G-quadruplex DNA are dictated by its sequence and greatly affected by environmental factors. The core guanine tetrads (G-tetrads) coordinate cations and display a strong conformational rigidity compared with the connecting loops. Although long loops linking the G-tetrads are typically disfavoured, when present, they provide a striking view of the dynamics of short, single-stranded DNA regions. In addition to their role in determining the stability of the G-quadruplex state, these loops are potential drug targets. In order to characterise accurately the dynamics of this DNA state, we apply the principles of structural ensemble determination developed in the last two decades for protein molecules to DNA molecules. We thus performed extensive molecular dynamics simulations restrained with NMR residual dipolar couplings to determine a structural ensemble of the human CEB25 minisatellite G-quadruplex, which contains a connecting loop of 9 nucleotides. This structural ensemble displays a wide set of arrangements for the loop and a compact, well-defined G-quadruplex core. Our results show that stacking interactions dominate over intra-residue contacts in the loop and strengthen the ability of the closing base pairs to confer a large thermodynamic stability to the structure.