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Dependence of DNA Polymerase Replication Rate on External Forces: A Model Based on Molecular Dynamics Simulations

Ioan Andricioaei ^*, Anita Goel ^* , Dudley Herschbach ^* and Martin Karplus ^* 

^* Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138 USA; Department of Physics, Harvard University, and Harvard MIT Joint Division of Health Sciences and Technology, Cambridge, Massachusetts 02138 USA; and Institut Le Bel, Université Louis Pasteur, Strasbourg, France

Correspondence: Address reprint requests to Martin Karplus, E-mail: marci{at}tammy.harvard.edu.

Molecular dynamics simulations are presented for a Thermus aquaticus (Taq) DNA polymerase I complex (consisting of the protein, the primer-template DNA strands, and the incoming nucleotide) subjected to external forces. The results obtained with a force applied to the DNA template strand provide insights into the effect of the tension on the activity of the enzyme. At forces below 30 pN a local model based on the parameters determined from the simulations, including the restricted motion of the DNA bases at the active site, yields a replication rate dependence on force in agreement with experiment. Simulations above 40 pN reveal large conformational changes in the enzyme-bound DNA that may have a role in the force-induced exonucleolysis observed experimentally.

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