Computational Core

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We will use computational techniques that were previously developed and tested by our research group in studies of DNA replication and related biochemical processes. These computer simulations will systematically examine changes in the activation barrier of the chemical step due to different factors including the effects of point mutations of distant pol B residues, to substitutions of the p-y bridging oxygen by the - C X Y - groups where X. Y = H, CH3, F, CI, Br or N3, and substitutions in the deoxyribose residues of the primer or dNTP nucleotides. Additionally, calculations of the substrate binding in its ground- and transition-state configurations will be investigated by proven computational strategies with extended simulation times. The results of the simulations (including TS structures and charge distributions as well as simulation protocols) will form a database that will include numerous experimentally-testable predictions along with the list of the assumptions and theoretical models that were used to generate these predictions. This database, which will be made accessible online, will be continually updated with new experimental and computational results, helping in selecting the best models and simulation strategies, and eventually to understanding of the functionally important properties of DNA polymerases at the atomic level. Additionally, the comparative studies will help in selecting the most effective approach for computational inhibitor and mutational screening.