Theoretical Studies Of The Interaction Of Diamidine Derivatives With DNA

The appearance of genetic medicines makes it possible for human to conquer all the diseases. So, more and more attention has been paid on the field of genetic medicines in the last few years. The outstanding biological function of polyamine drug molecules makes it become one of the hottest spots in the area of genetic medicine. In this paper, we mainly studied the interaction of polyamine drug molecules and DNA. It contains two parts:The first part is to explore the binding model of polyamine drug molecules and DNA and the second part is to study the binding model and conformational dynamics between reversible amine and nucleic acid.The first topic is to explore the best binding model of polyamine and DNA using the method of molecular docking. We choose DB75 and DB293 as parents and obtain other 40 small molecules by making some modifications of them. Density functional methods in B3LYP/6-31G (d, p) level is used for the optimization of ligands and then the RESP charge is calculated. At last, docking study is performed using the Autodock4 software. The result shows that ligands can bind into the minor groove of DNA and they prefer AT-rich sequences. Further study illustrates that mainly four factors are able to influence the binding results:(1) the curvature of ligand, (2) charge, (3) the kind of center atom, and (4) molecule length. The less the differences between the curvature of DNA and ligand are, the stronger the binding ability will be; The charge of the ligand can make a contribution to increase the electrostatic interaction; The kind of center atom will decide whether some key H-bonds could form between ligand and base pairs of DNA or not. And the increase of ligand length can strengthen the Van de Waal interaction between polyamine drug molecules and DNA obviously.The second topic is "Binding properties and conformational dynamics of reversible amidines with DNA from a theoretical view." We present here molecular dynamics simulations and DNA conformational dynamics for three reversible amidine-DNA addcuts. Our simulation results indicated that a DNA molecule bound by a reversible amidine produced a narrow and deep minor groove. The N-H and C-H groups in binding regions from reversible amidines play important roles on functioning as H-bond donors to N or O atoms of nucleobase located on the floor of the minor groove of DNA. DNA conformational dynamics in the vicinity of binding region were influenced significantly by the reversible amidine on a nanosecond time scale. Binding free energies calculated using MM_PBSA methods reveal that the binding interaction of a reversible amidine with DNA was enthalpically driven, associated with an entropic penalty during the binding process. The obtained results demonstrated that influence on the central heterocycle is greater than that of tail part for reversible amidines binding affinity to DNA. All of these findings not only provide useful information to better understand the binding properties of the reversible amidines but also give an ideas for design of novel amidine-based drug candidates.