Correlation between electron localization and metal ion mutagenicity in DNA synthesis from QM/MM calculations

DNA polymerases require two divalent metal ions in the active site for catalysis. Mg(2+) 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 used structural and topological analyses based on ab initio QM/MM calculations to study human DNA polymerase λ (Polλ) with different metals in the active site. Our results indicate a slightly longer O3'-Pα distance (∼3.6 Å) for most inhibitor cations compared to the natural and mutagenic metals (∼3.3-3.4 Å). Optimization with a larger basis set for the previously reported transition state (TS) structures (Cisneros et al., DNA Repair, 2008, 7, 1824.) gives barriers of 17.4 kcal mol(-1) and 15.1 kcal mol(-1) for the Mg(2+) and Mn(2+) catalyzed reactions respectively. 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. Theor. Comput., 2010, 6, 1048.) we have performed electron localization function (ELF) topological analyses. These analyses show 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 Mg(2+) metal. Population and multipole analyses on the ELF basins reveal that the electronic dipolar and quadrupolar polarization is significantly different with Mg(2+) compared to all other cations. Our results shed light at the atomic level on the subtle differences between Mg(2+), 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.