Minimum energy reaction profiles for the hydrolysis reaction of the cyclic guanosine monophosphate in water: Comparison of the results of two QM/MM approaches

Minimum energy pathways for the hydrolysis reaction of the cyclic guanosine monophosphate (cGMP) in water were calculated by using two versions of the quantum mechanics/molecular mechanics (QM/MM) theory. The first version corresponded to the electrostatical embedded cluster method, the second one referred to the effective fragment potential approach. In both cases the density functional theory methods (B3LYP/cc-pVDZ and PBE0/6-31G*) were applied to describe the QM subsystem composed of the cGMP substrate, the lytic water molecule and the chain of four water molecules participating in proton transfers. The shells of 301 explicit solvent water molecules (the MM subsystem) were simulated by using the TIP3P potential. Qualitatively, both QM/MM approaches resulted in similar minimum energy pathways: stationary points on the potential energy surface, corresponding to the reagents, products and reaction intermediate with the pentacoordinated phosphorus species, were located and the related saddle points separating these minimum energy structures were identified. Both computed minimum energy profiles correspond to the reaction route with a rate-limiting activation barrier much lower than that estimated previously for a direct attack of the lytic water molecule at the phosphorus center. The major difference in the profiles computed with both QM/MM approaches is due to the energy level of the reaction intermediate relative to that of the reagents.