(377c) A New Paradigm In Force Dependence In Single Molecule Experiments Unraveled By Molecular Simulations

High fidelity polymerases are efficient catalysts of phosphodiester bond formation during DNA replication/repair. We interpret molecular dynamics simulations of a polymerase bound to its substrate DNA and incoming nucleotide using a quasi-harmonic model to formulate a new model for studying the effect of external forces applied to the bound DNA on the kinetics of phosphoryl transfer. The origin of the force dependence is shown to be an intriguing coupling between slow, delocalized polymerase-DNA modes and fast catalytic site motions. Using non-cognate DNA substrates we show that the force dependence is context specific. We validate the simplying assumptions of our quasiharmonic model by performing mixed QMMM simulations of the polymerase catalysis reaction.