This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The field of MD on nucleic acids is now well into a second generation including solvent at ionic strengths relevant to in vitro experiments and in vivo phenomena. The results of MD on DNA are much improved, and provide a reasonable if not yet perfect description of nucleic acid dynamical structures in solution (Beveridge and McConnell 2000; Cheatham and Young 2001; MacKerell et al. 2000). In a larger sense, however, the field of MD on nucleic acids to date is a set of promising anecdotal cases. A broad range of studies, involving diverse sequences in both solution and crystalline conditions, must be carried out under tightly controlled simulation protocols and much extended run lengths so that ion motions are converged. Assessments of models must be carried to a higher level of resolution. This is newly feasible in the proposed project period. Agreement with experiment does not unequivocally prove a model is correct, so pushing MD models on DNA to failure or at least to the point of revealing limitations is essential to advance the science. At the same time, a number of issues of considerable interest in the structural biology of DNA, such as the nature of the hydration and ion atmosphere, sequence effects on structure and axis bending, the conformational landscape of the DNA double helix, structural adaptations of DNA on ligand binding and aspects of the relationship between dynamical structure and functional energetics are newly accessible to study by MD simulation. Thus, successful completion of the proposed research will lead to methodological improvements in simulation protocols and the informatics of analysis, advance our understanding of the dynamical structure of nucleic acids in solution, effects of sequence on DNA structure, conformational stability and axis bending important in molecular recognition processes, and contribute to an improved understanding of the thermodynamics of nucleic acid-ligand binding processes at the molecular level.
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