DNA and RNA exhibit an amazing degree of conformational polymorphism that is essential for their wide variety of biological functions, including gene regulation and expression. This conformational polymorphism is known to be dependent on both the environment of the DNA or RNA, including interactions with proteins, and on their base composition and sequence. It is therefore hypothesized that the conformational polymorphism of DNA and RNA is due to a balance between forces associated with intrinsic conformational properties and environmental interactions. Investigations are proposed to study this balance at an atomic level of detail using a combination of quantum mechanical (QM) and molecular dynamics (MD) based theoretical calculations. Toward this goal, further development of empirical force fields will be undertaken, focusing on improvements in additive models with respect to non A and B-forms, high energy conformations and base stacking and the development of a new non-additive force field by treating electronic polarizability via a Drude oscillator. These force fields, via MD simulations and potential of mean force (PMF) calculations, will be used to determine environmental contributions to RNA and DNA structure while QM calculations will be used to determine intrinsic conformational properties. Biological systems to be studied include the sequence dependence of the stability of GU mismatches in duplex RNA and base flipping in DNA alone and associated with methylation of DNA by the (cytosine-5)-methyltransferase from Hhal. These systems represent a variety of oligonucleotide conformations that are associated with different environmental interactions and sequence dependencies. From these investigations atomistic details of the forces stabilizing the different conformations will be obtained. Given the insights gained from these studies, unique conformational properties of DNA or RNA in mammalian versus prokaryotic systems or during viral gene regulation and expression will be better understood and will act as targets for the development of new classes of antibiotics or antivirals.