G-Quadruplex (GQ) is a secondary structural unit of DNA, formed at the telomere region of the chromosome with a high guanine content. It is reported that the GQs can hinder many biological processes. Thus, research thrives to explore the structural stability of GQs. Studies based on circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments established the vital role of cations such as K⁺ and Mg²⁺ in the stability of antiparallel G-quadruplexes (AGQs). However, there is a need to understand how stability in AGQ is attained in the presence of cations. Here, we employed molecular dynamics (MD) simulations, steered MD (SMD) simulations, and QM/MM calculations to understand the biophysical and electronic bases of the stability imparted to AGQs via cation binding. Our results showed that Mg²⁺ prefers to bind in the plane with the guanine tetrad, whereas K⁺ binds in between the AGQ tetrads. Thus, three Mg²⁺ cations or two K⁺ ions are needed to stabilize an AGQ molecule, where each and every tetrad binds to Mg²⁺ more robustly with a higher binding affinity. SMD revealed that the traversal of K⁺ through the AGQ central channel required less force than that of Mg²⁺, illustrating the presence of more strong interactions between Mg²⁺ and AGQ tetrads compared to K⁺. The stabilization in the AGQ tetrads due to cation binding is reassessed by employing ab initio simulations. Mixed QM/MM calculations confirmed that Mg²⁺ binds strongly to AGQ compared to K⁺, and it induces higher interactions between the guanine tetrads. However, K⁺ binding to AGQ induces a higher stabilization energy than Mg²⁺ binding to AGQ tetrads. Despite the higher binding energy, Mg²⁺ binding imparts lower stabilization to AGQ due to its unfavorable fermionic quantum energy.

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