The theoretical study of DNA-small molecule interaction : a microscopic perspective
Date of Issue2017
School of Physical and Mathematical Sciences
The microscopic studies of DNA always involve the interaction between DNA and small molecules. Previously, much work has been done in our group with regard to the projects, such as DNA charge transport (CT) in the ionic liquid, and the interaction between G-quadruplex and metal complex. Such researches provide much inspiration and perspective to tune the dynamic conformation of the secondary structure of DNA and thus adjust the properties of DNA upon the binding of small molecules. However, it seems necessary to explain such experimental results with the microscopic structural processes. Since experimental characterization of DNA conformation, especially with dynamic motion of nucleobase pairs, were extremely limited, theoretical and computational approaches would be the desired exploration to better understand the experimental data. With such a goal in mind, series computational studies have been done in this thesis. Chapter 1 will review the currently available computational methods to study the dynamic structures and interactions between small molecules and DNA on different spatial scales. The basic principles and algorithms will be reviewed firstly, followed by the examples of advances in DNA simulation which explored the different structural properties of DNA under various situations. In chapter 2, molecular dynamics accompanied by Principal Component Analysis (PCA) will be used to analyze the subtle conformational change of duplex DNA in water and hydrated ionic liquid. The results demonstrated the confining effects of ionic liquid to DNA conformation, and further comparison of internal parameters showed that the most vulnerable region of DNA resided in the G-C/A-T neighboring step, to which the cations showed binding affinity at the same time. Further QM/MM calculation in the following chapter 3 illustrated that ionic liquids can facilitate the charge transport (CT) rate by increasing the coupling between adjacent nucleobase pairs. The rate was estimated under flickering resonance model with the required parameters computed by DFTB (Density functional theory tight-binding) method. Such theoretical research confirmed our previous experimental results and can provide more insights into the relationship between CT rate and dynamic conformation of duplex DNA upon binding of solvent molecules. Varieties of metal complexes as the G-quadruplex binder will be introduced in chapter 4. The planar Pt(II) complexes with different side chains were first explored. By docking simulation, the stabilization effect of side chain was illustrated. Next, the theoretical research on octahedral Ru(II) complex confirmed the importance of z-axis ligands which located at the ion channel to stabilize G-quartet. Further the customized force field was built for a binuclear Pt complex and molecular dynamics was employed to explore the possible structure after cross-linking reaction between binuclear complex and G-quadruplex. In appendix, an experimental work about direct RNA-DNA FISH (fluorescent in-situ hybridization) was introduced. Using amino-labeled oligonucleotide probes, a simple, robust and low-noise method for simultaneous detection of RNA and DNA by fluorescence in situ hybridization was established. With this modified probes, we demonstrated that the method can be applied to study a wide range of RNA and DNA targets at the single-cell and single molecule level in cellular contexts.