DNA polymerases require two divalent metal ions in the active site for catalysis. Mg2+ has been confirmed to be the most probable cation utilized by most polymerases in vivo. Other metal ions are either potent mutagens or inhibitors. We have used structural and topological analysis based on ab initio QM/MM calculations to study human DNA polymerase ? (Pol?) with different metals in the active site. Our results indicate only minor structural changes with most inhibitor and mutagenic cations compared to the natural metal.  Using the polarized QM/MM wavefunctions, we have performed electron localization function (ELF) topological analyses relying on the key relation between the topological signature of a metal cation and its selectivity within biological systems (de Courcy et al.,  J. Chem. Theo. Comp., 6  , 1048 (2010)) . This analysis shows that all inhibitor and mutagenic metals considered, except Na+, present a ``split'' of the outer--shell density of the metal. This ``splitting'' is not observed for the non--mutagenic Mg2+ metal.  Population and multipole analyses on the ELF basins shows that the electronic polarization and hyper--polarization on the incoming nucleotide is significantly different with Mg2+ compared to all other cations.  Our results shed light at the atomic level on the subtle differences between Mg2+, mutagenic, and inhibitor metals in DNA polymerases.  These results provide a correlation between the electronic distribution of the cations in the active site and the possible consequences on DNA synthesis.

Insights on metal ion mutagenicity in DNA polymerase λ from ab initio QM/MM calculations

243rd National Meeting (2012)

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