How many tautomerization pathways connect Watson-Crick-like G*·T DNA base mispair and wobble mismatches?
In this study, we have theoretically demonstrated the intrinsic ability of the wobble G·T(w)/G*·T*(w)/G·T(w1)/G·T(w2) 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 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 [Formula: see text] transition state stabilized by the participation of the unique pattern of the five intermolecular O6(+)H⋯O4(-), O6(+)H⋯N3(-), N1(+)H⋯N3(-), N1(+)H⋯O2(-), and N2(+)H⋯O2(-) 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 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.
a Department of Molecular and Quantum Biophysics , Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine , 150 Akademika Zabolotnoho Str., Kyiv 03680 , Ukraine.|b Department of Molecular Biotechnology and Bioinformatics , Institute of High Technologies, Taras Shevchenko National University of Kyiv , 2-h Akademika Hlushkova Ave., Kyiv 03022 , Ukraine.
Ol'ha O
OO
Brovarets'
a Department of Molecular and Quantum Biophysics , Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine , 150 Akademika Zabolotnoho Str., Kyiv 03680 , Ukraine.|b Department of Molecular Biotechnology and Bioinformatics , Institute of High Technologies, Taras Shevchenko National University of Kyiv , 2-h Akademika Hlushkova Ave., Kyiv 03022 , Ukraine.
Dmytro M
DM
Hovorun
D000465:Algorithms; D020137:Base Pair Mismatch; D020029:Base Pairing; D004269:DNA, Bacterial / Q000737:chemistry* / Q000235:genetics; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D017354:Point Mutation
D004269:DNA, Bacterial; C036483:T-DNA
DPT; incorporation error; mutagenic tautomerization; spontaneous point mutation; structural switching; zwitterionic transition state