DNA polymerase is an enzyme that catalyses the synthesis of DNA molecules by matching complimentary deoxyribonucleoside triphosphates (dNTP) to the template DNA strand using the standard Watson-Crick (WC) base pair rules. However, when a non-complimentary dNTP diffuses into the active site during the polymerase dNTP sampling, the polymerase domain will transition from an open to an ajar conformation. Thus, forming a different non-standard hydrogen-bonded base-pairing arrangement called a wobble mispair. While the usual (canonical) A-T and G-C base pairs have a characteristic WC geometries, wobble mispairs, such as wobble(G-T) and wobble(A-C), distort this geometry which is normally correctly identified by the polymerase. While there are other sources of replication errors, the fidelity of replication primarily depends on the ability of polymerases to select and incorporate the correct complementary base (see Fig. ) and reject these wobble mispairs. However, it is proposed that the wobble mismatch can form alternative tautomeric configurations that can mimic the WC geometry and lead to erroneous DNA base matches, such as wobble(G-T)→G*-T, where G* is the tautomeric (enol) form of the G base. Watson-Cricklike mispairs have been observed in the active sites of DNA polymerases, and ribosomes in enzymatically competent conformations. Both NMR relaxation dispersion experiments and simulations indicate that the concentration of tautomeric mismatches in the cellular environment is significant and has a considerable impact on the replication fidelity of the polymerase. They have all demonstrated that the population of Watson-Crick-like G-T mispairs depends on the local environment, such as the base sequence and the local solvation environment.