DNA cleavage by endonuclease I-DmoI. A QM/MM study and comparison with experimental data provide indications on the environmental effects

Here, we present the theoretical–computational modelling of the free energy barrier of the phosphodiester bond cleavage as occurring in the mesophilic variant of endonuclease I-DmoI bound to DNA. Our data, obtained by means of hybrid quantum mechanics/molecular mechanics approach, indicate that the influence of the environment, exerted by the enzyme, the solvent and the DNA, shifts the mechanism towards a more dissociative reaction pathway, compared to the unperturbed reaction. The perturbation of the environment results in an earlier transition state of hydrolysis, i.e. more similar to reagents. By such an approach, we estimate that the enzyme lowers the phosphorus–oxygen bond break free energy barrier of about 7.9 kcal/mol compared to the gas phase, which turns out to be consistent with experimental data. Such an approach points out the importance of an extended and accurate treatment of the environmental effects in the modelling of chemical reactions and confirms the reliability of our procedure in the modelling of important biochemical processes at a limited computational cost.