This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. An allocation of computer time on Anton is requested to investigate very significant methodological and sampling limitations with molecular dynamics (MD) simulations of the structure and dynamics of DNA and protein-DNA complexes. The issues are of a magnitude that is likely only and most thoroughly addressed with a multi-group, """"""""divide and conquer"""""""" approach. This proposal is submitted on behalf of the ABC consortium, an international group led by senior investigators with considerable experience with MD on nucleic acids in various theoretical and applied contexts. The simulations will be performed on Anton by the USA-based members of the consortium, and the results will be shared with others in the ABC Consortium for analysis, consideration of the functional implications of the results, and the preparation of publications. The major objectives of our proposed studies is to utilize ~10 micro-second (?s) MD simulations to fully characterize a) the structure and dynamics of the thermally accessible substates of DNA, the relaxation times of key dynamical quantities and convergence properties of the dynamical structure, and interactions with other molecules (salt, water, etc) and b) the corresponding issues that will be encountered in applications of all-atom, full solvent MD to the study of protein DNA complexes. Preliminary studies on each of the systems selected for study are provided in previously published articles from the various participants, and tools are in place for conformational and helical analyses, principle component analyses, and methods for sharing and distribution of results via relational data bases.
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