How many tautomerization pathways connect Watson–Crick-like G*·T DNA base mispair and wobble mismatches?
2015-10-08T18:37:28Z (GMT) by
<div><p>In this study, we have theoretically demonstrated the intrinsic ability of the wobble G·T(w)/G*·T*(w)/G·T(w<sub>1</sub>)/G·T(w<sub>2</sub>) and Watson–Crick-like G*·T(WC) DNA base mispairs to interconvert into each other <i>via</i> the DPT tautomerization. We have established that among all these transitions, only one single G·T(w) ↔ G*·T(WC) pathway is eligible from a biological perspective. It involves short-lived intermediate – the G·T*(WC) base mispair – and is governed by the planar, highly stable, and zwitterionic transition state stabilized by the participation of the unique pattern of the five intermolecular O6<sup>+</sup>H⋯O4<sup>−</sup>, O6<sup>+</sup>H⋯N3<sup>−</sup>, N1<sup>+</sup>H⋯N3<sup>−</sup>, N1<sup>+</sup>H⋯O2<sup>−</sup>, and N2<sup>+</sup>H⋯O2<sup>−</sup> H-bonds. This non-dissociative G·T(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 <i>via</i> 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.</p></div>