Extended-sampling QM/MM simulation of biochemical reactions involving P-N bonds.

The description of the phosphate group and its reactions with nitrogen species appears to be challenging using semi-empirical quantum chemical methods, and this holds for DFTB3 too. A new parameterization of DFTB3, consisting of a new P-N repulsive function, has been developed to improve its performance for reactions in which a P-N bond is replaced by a P-O bond or vice versa . Extended-sampling QM/MM simulations using the new parameterization of DFTB3 represent biochemical phosphorylation and hydrolysis reactions involving P-N bonds accurately. The parameter set is benchmarked on a reaction modeling the autophosphorylation of histidine, and is applied to study the complex mechanism of the acidic hydrolysis of an anticancer drug, as well as to the autophosphorylation of a genuine histidine kinase protein.