<scp>DFT</scp> Analysis of Stacking Interactions and Cyclic H‐Bond Cooperativity in G‐Quadruplexes

Molecular stacking, especially π-stacking and H-bond interactions, is important in various biochemical and material science fields. Stacking interactions are used to design supramolecular assemblies such as host-guest complexes. Stacking interactions also play a crucial role in the structure and function of biomolecules like DNA, RNA, and proteins. G-quadruplex, a non-canonical DNA structure that is essential for a number of biological functions, such as gene control, telomere preservation, and DNA replication, is stabilized by stacking and H-bond interactions. They are particularly important in cancer development as potential drug targets. Additionally, they are used in drug delivery systems and stimuli-responsive materials. This study aims to cast light on the structure, energetics, and various intermolecular interactions involved in five differently stacked G-quadruplex structures. The various computational methods employed for the calculations and analysis are Energy Decomposition Analysis using DFT calculations and Quantum Theory of Atoms in Molecules (QTAIM) at M062X/6-311G(d,p) level in gas phase. The calculations performed show that the parallel conformations of G-quadruplex are more stable than the other structures containing anti-parallel conformations. Energy decomposition analysis suggests that with respect to stability, the parallel structure benefits more from stacking interactions over the anti-parallel one. However, the H-bond cooperativity contribution in the cyclic G-quadruplex is found to be almost the same in both conformations. The structural stability is further analyzed by the QTAIM method, which shows that the greater number of stacking interactions in the parallel structure makes it more stable than the anti-parallel structure. A detailed examination of the stacking interaction revealed its electrostatic nature.