The long term objective of this project is the theoretical prediction of the conformational transitions which can be ihnduced in DNA by changes in the solution environment, or by the binding of ligands or proteins. Distinct conformational preferences are expected to be induced in different sequences of nucleotide bases and modified bases by variations in their local environment. Understanding the conformational properties of DNA sequences may aid our understanding of sequence specific recognition of DNA. To accomplish this objective, we plan to extend present theoretical techniques which have been primarily developed for structural studies of non-polar molecules. The extension involves treating the polyelectrolyte character of nucleic acids explicitly by recognizing that the anionic phosphate groups attract a three dimensional shroud of counterions which is inseparable from the nucleic acid. We propose to develop a potential function which models the entire DNA-counterion system. To accomplish this we will develop a highly accurate description of the structure of the counterion shroud around different conformations and base sequences of DNA as a function of electrolyte concentration. This description will be used to create a point charge model for the structured counterion environment which will be used as an electrostatic energy function for the DNA-counterion system. We will integrate this electrostatic potential into existing forms of empirical potential functions performing a limited optimization of parameters to obtain a self-consistent potential function which describes the energy of a segment of DNA as a function of conformation and solution environment. Ab initio extended basis set calculations on the geometry of complexes between divalent cations and phosphate groups on the presence of a limited number of water molecules will be done, to determine the nature of this association. Applications of the polyelectrolyte theory will provide definitive results regarding the accumulation of counterions around DNA as the ionic strength is increased. Incorporation of this theory into a balanced potential function should allow predictions of sequence specific conformation transitions as a function of ionic strength.
