Investigation of ion-dependent conformational changes of DNA G-quadruplex: Molecular dynamics simulation

Single-stranded nucleic acids have high flexibility and can be folded in various ways. Recently, the importance of DNA G-quadruplex (G4) has been emphasized in gene regulation and telomere maintenance in vivo. G4 can form various conformations in one sequence depending on different conditions, such as changes in cations, pH, and crowding, and there are over 700,000 regions exist that could be G4 in the human genome. In particular, cations located in the core of G4 and having a great influence on stability are the most investigated factor for the conformation of G4. Despite the crucial role of cations, the detailed mechanism of ion-dependent conformational change of G4 is not reported yet. Here, we performed all-atom molecular dynamics (MD) simulation to check the stability of the G4 structure affected by the core-forming cations, using two representative crystallographically resolved G4 structures with the same sequence but different cations. Calculating the free energy difference of interconversion of Na⁺ and K⁺ using the alchemical transformation method, we identify the molecular features that play a key role in the stability of G4 structure and give critical assessments on the existing force fields for simulating non-helical DNA structure with strong electrostatic interactions.