G-quadruplexes (GQs) are important therapeutic targets in cancer due to their diverse biochemical roles. Molecular dynamics (MD) simulation is an essential tool for the property research of GQs. However, conventional MD simulations often suffer from overestimated ion repulsion, unstable loop regions, and bifurcated hydrogen bonds in G-tetrads. To address the above issues, we developed a polarized nucleic acid-specific charge (PNC) model based on fragment quantum chemistry. MD simulations compared standard non-polarized force fields (bsc0, bsc1, OL15, OL21) against PNC-based polarized versions in GQ and hairpin systems. In the 1JRN GQ system, non-polarized force fields showed a higher RMSD/RMSF, bifurcated hydrogen bonds, and losses of coordinating ions—issues observed across five K + and four Na + parameter sets. In contrast, MD simulations under PNC maintained stable loop structures, preserved central K + /Na + ions within the channel, and reproduced crystal-like hydrogen bonding. Furthermore, in the MD simulations of the 5M1W system, where a single-stranded DNA folds into a hairpin structure which is a key intermediate likely involved in GQs folding, compared within non-polarized force fields, the free energy landscapes generated using PNC-based force fields show improvements to varying degrees. Overall, for GQ or hairpin systems, the inclusion of polarization effects should be considered indispensable in MD simulations, as it is critical for maintaining structural stability and yielding a more reliable conformational landscape for evaluating thermodynamic properties to a certain extent.
Tian et al. (Fri,) studied this question.