Browsing by Author "Salsbury, Alexa M."

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    Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations
    Salsbury, Alexa M.; Lemkul, Justin A. (2021-06-01)
    Nucleic acid-ion interactions are fundamentally important to the physical, energetic, and conformational properties of DNA and RNA. These interactions help fold and stabilize highly ordered secondary and tertiary structures, such as G-quadruplexes (GQs), which are functionally relevant in telomeres, replication initiation sites, and promoter sequences. The c-kit protooncogene encodes for a receptor tyrosine kinase and is linked to gastrointestinal stromal tumors, mast cell disease, and leukemia. This gene contains three unique GQ-forming sequences that have proposed antagonistic effects on gene expression. The dominant GQ, denoted c-kit1, has been shown to decrease expression of c-kit transcripts, making the c-kit1GQa promising drug target. Toward disease intervention, more information is needed regarding its conformational dynamics and ion binding properties. Therefore, we performed molecular dynamics simulations of the c-kit1 GQ with K+, Na+, Li+, and mixed salt solutions using the Drude-2017 polarizable force field. We evaluated GQ structure, ion sampling, core energetics, ion dehydration and binding, and ion competition and found that each analysis supported the known GQ-ion specificity trend (K+ > Na+ > Li+). We also found that K+ ions coordinate in the tetrad core antiprismatically, whereas Na+ and Li+ align coplanar to guanine tetrads, partially because of their attraction to surrounding water. Further, we showed that K+ occupancy is higher around the c-kit1 GQ and its nucleobases than Na+ and Li+, which tend to interact with backbone and sugar moieties. Finally, we showed that K+ binding to the c-kit1GQ is faster and more frequent than Na+ and Li+. Such descriptions of GQ-ion dynamics suggest the rate of dehydration as the dominant factor for preference of K+ by DNA GQs and provide insight into noncanonical nucleic acids for which little experimental data exist.
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    Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes
    Salsbury, Alexa M.; Michel, Haley M.; Lemkul, Justin A. (American Chemical Society, 2022-07-12)
    Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme-GQ interactions and dynamics important for potential drug design. GQs have a characteristic tetrad core, which is connected by loop regions. Within this architecture are G-hairpins, fold back motifs that are thought to represent the first intermediate in GQ folding. To better understand the relationship between G-hairpin motifs and GQs, we performed polarizable simulations of a two-tetrad telomeric GQ and an isolated SC11 telomeric G-hairpin. The telomeric GQ contains a G-triad, which functions as part of the tetrad core or linker regions, depending on local conformational change. This triad and another motif below the tetrad core frequently bound ions and may represent druggable sites. Further, we observed the unbiased formation of a G-triad and a G-tetrad in simulations of the SC11 G-hairpin and found that cations can be partially hydrated while facilitating the formation of these motifs. Finally, we demonstrated that K+ ions form specific interactions with guanine bases, while Na+ ions interact nonspecifically with bases in the structure. Together, these simulations provide new insights into the influence of ions on GQs, G-hairpins, and G-triad motifs.