? DNA polymerases are responsible for the faithful copying of genetic information from one cell generation to the next. Errors in replication can lead to mutations detrimental to the survival of the organism. The goal of the proposed research is to gain a microscopic understanding of DNA replication process. In particular, we will investigate the polymerase-mediated translocation step during DNA replication. Using a set of reaction path finding methods, free energy calculations, and normal mode analyses, we will determine the key residues of the polymerase and their role in translocation, as well as the source of energy and the mechanism for its conversion into mechanical work in this process. Several analytical and numerical methodologies will be developed to carry out the project, which will be relevant to a broad range of biological problems. The research has implications for the treatment of viral and bacterial infections that target the DNA replication process, e.g., that of the HIV virus. It also could assist in the design of therapies for various diseases caused by errors in the replication machinery, such as cancer, premature aging, and neurodegenerative diseases. ? ?
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