期刊
BIOPHYSICAL JOURNAL
卷 120, 期 11, 页码 2249-2261出版社
CELL PRESS
DOI: 10.1016/j.bpj.2021.03.022
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资金
- National Institutes of Health [R35GM133754]
- Thomas F. and Kate Miller Jeffress Memorial Trust (Bank of America, Trustee)
- U.S. Department of Agriculture National Institute of Food and Agriculture [VA-160092]
- American Association of University Women (American Dissertation Fellowship)
Nucleic acid-ion interactions play a crucial role in the structure and function of DNA and RNA. Molecular dynamics simulations reveal that potassium ions bind more effectively than sodium and lithium ions in G-quadruplexes, with a faster binding rate.
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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