Figure 7. Translocation‐regulated model of active‐site switching.

The DNA synthesis pathway in the blue box is the canonical pathway of nucleotide incorporation cycles. Nucleotide binding to the post‐translocation state of DNAP is followed by fingers closing conformational change and the chemical step of nucleotide incorporation that result in the extension of the primer‐end by one nucleotide. Upon PPi dissociation, the DNAP ends up in the pre‐translocated state (fingers open). The primer‐end in the pre‐translocated state can partition into the exonuclease active site, or the DNAP can translocate to the post‐translocated state to repeat the next cycle of nucleotide incorporation. We assumed here that the pre‐ to post‐translocation step is a rapid equilibrium step. Occasionally, the DNAP encounters translocation hurdles that create Pol‐inhibited states. These are branched out of the normal DNA synthesis pathway and are not competent in translocation or dNTP binding but competent in shuttling the primer‐end in the Exo‐site and excising the primer‐end nucleotide. After excision of the primer‐end, the DNAP is shown to return to the post‐translocation state. While DNA synthesis resumes via the normal pathway after excision event due to misincorporation, the DNAP idles in case of template lesions and other replication barriers until the problem is resolved.