THEORETICAL STUDIES ON THE MECHANISM OF CYCLIC NUCLEOTIDE MONOPHOSPHATE HYDROLYSIS WITHIN PHOSPHODIESTERASES

As the only metabolizing enzyme for the degradation of second messenger cAMP and cGMP, phosphodiesterase (PDE) has been the clinical target of various human diseases. But the hydrolysis procedure of PDE is still unclear. To investigate the mechanism of PDE catalysis, three types of PDE (PDE4d, PDE5a and PDE10a) were selected and studied by using molecular dynamics (MD) simulation and quantum mechanics (QM) calculation methods. MD Simulation results indicate that different PDEs share a similar hydrolysis area in the active sites, and the phosphate parts of cyclic nucleotides take the same orientation and are partly surrounded by water molecules. Based on the statistical data of MD simulation, the QM calculation models were built. The calculation results indicate that in aqueous solution, the nucleophile hydroxide ion that attacks the phosphor atom of the cyclic nucleotide in the hydrolysis may migrate between the two metal ions in the active site. To help the ring-open reaction, it is the water molecule that provides proton to the O3' atom of cyclic nucleotide, and generates another hydroxide ion complexed with the metal ion.