Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

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 proto-oncogene 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-kit1 GQ a 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-kit1 GQ 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.