DNA and RNA exhibit an amazing degree of conformational polymorphism that is essential for their wide variety of biological functions, including replication and gene regulation. The importance of this polymorphism in the biological functions of oligonucleotides is becoming more evident as discoveries of non-canonical structures that play essential roles in both eukaryotic and prokaryotic organisms are identified. The variety of conformations assumed by oligonucleotides, be they either canonical or non- canonical, are dictated by a balance of interactions with their environment, including interactions with small molecules and proteins, and of their intrinsic conformational properties, largely dictated by the base sequence. In the proposed study this balance will be investigated at an atomic level of detail using a combination of quantum mechanical (QM) and molecular dynamics (MD) based theoretical calculations. Towards this goal, further development of empirical force fields will be undertaken, focusing on improvements in the currently available CHARMM27 additive model and the development of a novel non- additive force field in which electronic polarizability is explicitly treated via classical Drude oscillators. These force fields, via MD simulations and potential of mean force (PMF) calculations, will be used to determine environmental contributions to RNA and DNA properties while QM calculations will be used to determine intrinsic conformational properties. Biological systems to be studied include a variety of canonical forms of DNA and RNA as well as non-canonical forms including bulges, hairpins and a RNA riboswitch. These systems represent a variety of oligonucleotide conformations that are associated with variations in sequence and environment, including interactions with ions. From these investigations atomistic details of the forces stabilizing the different conformations will be obtained. Given the insights gained from these studies, conformational properties of DNA or RNA relevant to their biological activity will be elucidated. These new finding will ultimately be used to rationally target oligonucleotides, such as the ribosome and riboswitches, in order to create, for example, novel antibiotics. Moreover, the more accurate empirical models of nucleic acids developed in the proposed work will allow more realistic MD based studies of these systems by the theoretical chemistry and biophysics communities.
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