Polarizable Molecular Dynamics Simulations of Two Oncogene Promoter G-Quadruplexes: Effect of Primary and Secondary Structure on Loop and Ion Sampling.

G-quadruplexes (GQs) are highly ordered nucleic acid structures that play fundamental roles in regulating gene expression and maintaining genomic stability. GQs are topologically diverse and enriched in promoter sequences of growth regulatory genes and proto-oncogenes, suggesting that they may serve as attractive targets for drug design at the level of transcription rather than inhibiting the activity of the protein products of these genes. The promoter contains three adjacent GQ-forming sequences that have proposed antagonistic effects on gene expression and thus are promising drug targets for diseases such as gastrointestinal stromal tumors, mast cell disease, and leukemia. Because GQ stability is influenced by primary structure, secondary structure, and ion interactions, a greater understanding of GQ structure, dynamics, and ion binding properties is needed to develop novel, GQ-targeting therapeutics. Here, we performed molecular dynamics simulations to systematically study the and GQs, evaluating nonpolarizable and polarizable force fields (FFs) and examining the effects of base substitutions and cation type (K, Na, and Li) on the dynamics of their isolated and linked structures. We found that the Drude polarizable FF outperformed the additive CHARMM36 FF in two- and three-tetrad GQs and solutions of KCl, NaCl, and LiCl. Drude simulations with different cations agreed with the known GQ stabilization preference (K > Na > Li) and illustrated that tetrad core-ion coordination differs as a function of cation type. Finally, we showed that differences in primary and secondary structure influence loop sampling, ion binding, and core-ion energetics of GQs.