How many tautomerization pathways connect Watson-Crick-like G*center dot T DNA base mispair and wobble mismatches?

摘要

In this study, we have theoretically demonstrated the intrinsic ability of the wobble GT(w)/G*T*(w)/GT(w(1))/GT(w(2)) and Watson-Crick-like G*T(WC) DNA base mispairs to interconvert into each other via the DPT tautomerization. We have established that among all these transitions, only one single GT(w)G*T(WC) pathway is eligible from a biological perspective. It involves short-lived intermediate - the GT*(WC) base mispair - and is governed by the planar, highly stable, and zwitterionic TSG center dot T(W)<-> G center dot T*(WC)G+center dot T- transition state stabilized by the participation of the unique pattern of the five intermolecular O6(+)HO4(-), O6(+)HN3(-), N1(+)HN3(-), N1(+)HO2(-), and N2(+)HO2(-) H-bonds. This non-dissociative GT(w)G*T(WC) tautomerization occurs without opening of the pair: Bases within mispair remain connected by 14 different patterns of the specific intermolecular interactions that successively change each other along the IRC. Novel kinetically controlled mechanism of the thermodynamically non-equilibrium spontaneous point GT/TG incorporation errors has been suggested. The mutagenic effect of the analogues of the nucleotide bases, in particular 5-bromouracil, can be attributed to the decreasing of the barrier of the acquisition by the wobble pair containing these compounds of the enzymatically competent Watson-Crick's geometry via the intrapair mutagenic tautomerization directly in the essentially hydrophobic recognition pocket of the replication DNA-polymerase machinery. Proposed approaches are able to explain experimental data, namely growth of the rate of the spontaneous point incorporation errors during DNA biosynthesis with increasing temperature.