Theoretical studies probing the structural, dynamic and solvation properties of DNA and modified DNA analog

DNA and modified DNA analogs were investigated using theoretical methods such as quantum mechanics (QM) and molecular dynamics (MD). Novel empirical force field parameters were developed for phosphoramidate, carbocyclic, and 2'-fluoro-substituted DNA analogs. The intrinsic, dynamic, and hydration properties of N3'phosphoramidate-substituted DNA were analyzed to explain its unique structural and biochemical properties. The conformational properties of 2'-fluoro-substituted sugars, especially for bond rotation around the chi dihedral and the sugar pucker were analyzed in the context of their biochemical properties. The effect of substitution of abasic carbocyclic sugars at the target site in DNA interacting with the Hha I cytosine-C5-methyltransferase enzyme was analyzed using QM calculations, MD simulations, and supporting biochemical studies and used to corroborate a structural model for the catalytic mechanism of the enzyme. The effects of single and multiple substitutions of pseudorotationally constrained sugars in the DNA backbone are analyzed to understand changes in bending and hydration properties. A novel reaction coordinate for base flipping was designed and implemented to determine the free energy of base flipping in DNA. The structural and environmental properties contributing to the free energy profile of the base flipping process were studied.