Ravi Radhakrishnan and Ravindra Venkatramani. Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, 240 Skirkanich Hall, Philadelphia, PA 19104
Polymerases are proteins that replicate DNA not only with remarkable efficiency but also with high accuracy. They are important players in the error-free DNA replication process that is central to the integrity of our genome. Through computer simulations of the dynamics of a polymerase DNA complex at atomic resolution we suggested that an intriguing dynamical coupling between the cooperative motion of polymerase and DNA atoms may play a significant role in aiding and abetting the chemical reaction (chemical step) that leads to nucleotide incorporation during DNA replication. We also suggest that the coupling is disrupted to varying extents in a context-specific fashion, i.e., when the inserted nucleotide is not complementary to the template base (mispair) or when the template base in the DNA is oxidatively damaged. Using an elastic response formalism, we also show that as a direct consequence of the dynamical coupling, the rate of the chemical step is dependent on the applied force on the DNA (template) strand, and that the force-dependence is also context-specific. The motivation for performing computational studies on atomically-detailed systems is to challenge the status quo, i.e. the existing paradigm which attributes the force-response to elasticity changes between single and double-stranded DNA and hence does not predict a context specific force-response. Our finding that the dynamic coupling resulting from the atomic details of the protein architecture is directly responsible for the force-dependence of the rate is in stark contrast to the DNA-elasticity paradigm. Our predictions can be tested directly through single-molecule experiments.