The goal of this work is to understand the influence of chemical architecture and environment; i.e., the constituent atoms and chemical bonds, on the conformation, properties, and interactions of nucleic acids. The research is computational involving analyses of high resolution structural data, knowledge-based and classical (all-atom) energy calculations, molecular modeling, developments and applications of polymer chain statistics and polyelectrolyte theory, and Gaussian and Monte Carlo simulation studies. Current interests focus on ligand-induced distortions of B-DNA important to its manipulation and control during genetic processes: (1) the transitions of B-DNA to three closely related helical formsuA-DNA, which is implicated in enzymatic cutting and sealing of the chain backbone, C-DNA, which is used in global packaging, and TA-DNA, a severely bent and unwound form relevant to control of transcription; (2) the basepair opening needed to """"""""melt"""""""" the duplex during its repair, replication, and transcription; and (3) the helix-helix interactions associated with DNA recombination and packaging. Each problem is attacked with a two pronged approach that synthesizes knowledge of conformation and ligand contacts gained in the systematic analysis of known high resolution DNA structures with theoretical assessment of the energetic contributions that underlie these states. The latter calculations are guided by ligand-binding patterns characteristic of specific conformational states. Both knowledge and physics-based potentials are used to assess the energy, the former primarily for the study of sequence-dependent chain properties and for effective simulations of large-scale structural changes, and the latter to decipher the atomic basis of observed conformational states. In order to update and test the knowledge-based potentials, new methods are being developed to assess a range of configuration-dependent chain properties (probabilities of ring closure, distances between fluorescent dyes tethered to the ends of double helices, nucleosome positioning). In view of the dominant role of electrostatics on DNA conformational energy, the electronic structure of the DNA bases, sugars, and phosphates and relevant ligand fragments is being reinvestigated using density functional theory. New approaches to build atomic models of DNA that take explicit account of the closely associated cloud of bound waters are also under development.
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