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It was recently discovered that, besides well-known G-quadruplexes and i-motifs,DNA may adopt another type of noncanonical structure called AGCGA-quadruplexes.H ere, the folding of the VK2 fragment from the regulatory region of the PLEKHG3 gene is studied and, for the first time,t he energetic contributions that stabilizet his unique fold are described. Similarly to the B-DNA, it is stabilized by hydrophobic desolvation and, in contrast to G-quadruplexes,also by specific binding of water molecules.C ompared to B-DNA, VK2 folding is enthalpically less favorable due to poorer basestacking interactions,r esulting in substantial conformational flexibility.This entropically favorable conformational "breathing" stabilizes the AGCGA-quadruplexes.I nc onclusion, AGCGA-quadruplexes have ad istinguishing thermodynamic fingerprint and the corresponding driving forces enabling their folding are consistent with the observed structural features.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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The structural polymorphism of G-quadruplex nucleic acids is an important factor in their recognition by proteins and small-molecule ligands. However, it is not clear why the binding of several ligands alters G-quadruplex topology. We addressed this question by following the (un)folding and binding of the human telomeric fragment 5′-(GGGTTA)3GGGT-3′ (22GT) by calorimetry (DSC, ITC) and spectroscopy (CD). A thermodynamic analysis of the obtained data led to a detailed description of the topological phase space of stability (phase diagram) of 22GT and shows how it changes in the presence of a specific bisquinolinium ligand (360A). Various 1:1 and 2:1 ligand–quadruplex complexes were observed. With increasing temperature, the 1:1 complexes transformed into 2:1 complexes, which is attributed to the preferential binding of the ligand to the folding intermediates. Overall, the dissection of the thermodynamic parameters in combination with molecular modelling clarified the driving forces of the topological quadruplex transformations in a wide range of ligand concentrations and temperatures.