Differential effect of alkali metal ions on the structure and stability of DNA G-Quadruplexes with potential role in the regulation of gene expression

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Henry Ikechukwu Ochije (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Ethan Will Taylor

Abstract: G-quadruplexes (G-QPX) have been the subject of great interest in research due to their exclusive structural configuration, functionality and potential roles in biological applications particularly gene regulation and Nano-switch applications. Initial research has identified the presence of G-Quadruplex in the promoter regions of the human genome as well as untranslated regions of RNA. Promoter regions of human DNA have been found to be rich in Guanine which is one of the essential nucleotides required for the formation of G-Quadruplex structures with the potential to regulate gene activities, thereby acting as a biological switch by either allowing or disrupting the binding of transcription factors during gene expression. Ions such as potassium and sodium have been known to play key role in the formation and stability of G-Quadruplex leading to its potential role in up regulation and down regulation of transcription factors by interfering with their ability to bind on their specific binding sites on DNA. Though a variety of research has shown the potential role of alkali metal ions in the stability of quadruplex structure, not much has been done on the effect of concentration of theses ions on the structure of G-Quadruplex. The focus of this research is to understand the differential effect of alkali metal ions on the structure and stability of DNA G-Quadruplexes with potential role in the regulation of gene expression. Three alkali ions have been employed in this research, sodium, potassium ion because of their potential role in cell activities and Lithium ion because of its potential use in therapeutics. We also worked with four different modified crystal structures of the complex human telomeric repeat G-quadruplex (4fxm,1xav,217v and 2hri) In silico. The study was done under different ion concentration (50,100,150 and 160 mM). Different computational analysis was done on the structural change of GQuadruplex DNA with change in ion concentration using Gromacs computational software and algorithms. The obtained result suggests different response in structural change of G-Quadruplex DNA to changes in concentration of different ions. The effect of lithium ion on the structure of G-quadruplex has been an area of debate in the literature. Our results show that different G-Quadruplex and structures respond to variations in ion concentration differently, with some alkali ions favoring stability at lower concentration and acting differently at higher concentration. We observed deviations or structural changes in 4fxm G-Quadruplex with the three ions used in the simulation, sodium ion caused the most structural change, followed by lithium and potassium, making potassium more favorable in terms of structural change and stability. The same analysis was carried out on 1XAV G-Quadruplex, it also suggests lithium caused the most structural change followed by sodium and potassium, which further confirms potassium favors structural stability more than the other two ions (Li and Na+). A different result was observed on the structure of another G-Quadruplex 217v, the analysis shows a different response compared to the initial results, lithium caused the most structural change followed by potassium and sodium respectively. This could potentially tell that different G-Quadruplex structures may have a different response to variations in ions and ion concentration. Overall, potassium ion seems to favor GQuadruplex structural stability more than sodium and lithium. Lithium seem to cause more destabilizing effect at lower concentration and acts as stabilizing agent at higher concentration in some G-Quadruplex structures.

Additional Information

Publication
Dissertation
Language: English
Date: 2018
Keywords
Effect of Alkali Metal Ions, G-quadruplexes, Potential Role in the Regulation of Gene, Regulation of Gene Expression, Stability of DNA G-Quadruplexes, Structure and Stability of DNA
Subjects
Quadruplex nucleic acids
Alkali metal ions
Gene expression

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