DFT Analysis of Stacking Interactions and Cyclic H-Bond Cooperativity in G-Quadruplexes

Area of Science:

• Biochemistry
• Material Science
• Computational Chemistry

Background:

• Molecular stacking, including π-stacking and H-bond interactions, is fundamental in biochemistry and material science.
• G-quadruplex structures, stabilized by stacking and H-bonds, are vital for biological functions and are key targets in cancer research.

Purpose of the Study:

• To investigate the structure, energetics, and intermolecular interactions of five distinct G-quadruplex conformations.
• To elucidate the role of stacking and H-bond interactions in G-quadruplex stability.

Main Methods:

• Density Functional Theory (DFT) calculations at the M062X/6-311G(d,p) level in the gas phase.
• Energy Decomposition Analysis (EDA) to quantify interaction contributions.
• Quantum Theory of Atoms in Molecules (QTAIM) to analyze structural stability and interaction types.

Main Results:

• Parallel G-quadruplex conformations exhibit greater stability compared to anti-parallel ones.
• Stacking interactions contribute more significantly to the stability of parallel G-quadruplex structures.
• H-bond cooperativity is comparable in both parallel and anti-parallel cyclic G-quadruplex conformations.
• QTAIM analysis confirms that increased stacking interactions in parallel structures enhance their stability.
• Stacking interactions in G-quadruplexes are primarily electrostatic in nature.

Conclusions:

• Parallel G-quadruplex structures are thermodynamically favored due to superior stacking interactions.
• Understanding these interactions is essential for designing G-quadruplex-based therapeutics and materials.
• The electrostatic nature of stacking interactions offers insights for molecular design.