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Team investigates polymerase-beta actions in DNA duplicationStory posted December 6, 2006  The active site of DNA polymerase β in the crystal closed complex. Black dashed lines represent the hydrogen bonds and the ligand binding for the catalytic and nucleotide-binding Mg2+ ions. The key distances Pα—O3', Mg2+(cat.)—O3', Mg2+(cat.)-O1α, and Mg2+(cat.)—OD2-Asp256 are labeled A, B, C, and D, respectively. The region studied by the QM and QM/MM methods is highlighted in yellow. Image courtesy of Tamar Schlick, New York University. When DNA duplicates itself, the double helix unzips, and the linked pairs pop apart. The two component strands then act as templates for twins of the original unit. Extra nucleotides in the cell line up next to their complements on the template strand. Tamar Schlick, her team at New York University, and collaborators who include Sam Wilson and Bill Beard at the National Institute of Environmental Health Sciences use NCSA's Tungsten cluster to analyze the role that the enzyme polymerase-beta plays in ensuring complementary nucleotides are placed with one another. DNA replication is crucial for organisms to maintain genome integrity from generation to generation. Previous studies by the team showed that movement of the polymerase's subdomains are a sequence of subtle motions that involve key proteins and ions, rather than a single concerted event. In the fall of 2005, they published in the Journal of the American Chemical Society the sequence of events that contributes to correct (guanine to cytosine) or incorrect (guanine to adenine) nucleotide insertion. Their findings imply a possible "kinetic checkpoint" that discriminates proper nucleotides from improper nucleotides. This check takes place after the polymerase changes shape but before chemical reactions incorporate the nucleotide into the forming DNA strand. This work was made possible by developing the transition path sampling method for the first time for complex biomolecular systems, as reported in the Proceedings of the National Academy of Sciences in 2004. This article described the sequential residue rotations that follow in the conformational closing pathway for the correct base incorporation. The team is now investigating details of the chemical reaction for polymerase-beta with quantum and hybrid quantum/classical mechanics simulations. They are also conducting related studies for other DNA polymerases that are shedding further insights into polymerase mechanisms. |
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