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

作者：Alexa M. Salsbury, Tanner J. Dean, Justin A. Lemkul · 发表于：Journal of Chemical Theory and Computation · 年份：2020 · DOI：10.1021/acs.jctc.0c00191 · 被引用次数：34 · 研究领域：DNA and Nucleic Acid Chemistry、Advanced biosensing and bioanalysis techniques、RNA and protein synthesis mechanisms

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 c-kit 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 c-kit2 and c-kit* 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 illustrate...