Study on the hydrolysis mechanism of phosphodiesterase 4 using molecular dynamics simulations

We carried out NPT molecular dynamics simulations in an explicit solvent to better understand the mechanism of cyclic adenosine monophosphates (cAMP) hydrolysis by phosphodiesterase 4 (PDE4) enzyme on atomic details and to obtain information on the dynamics characteristic of the catalytic domains of PDE4. In analyzing the water hydrogen-bond network around the active site, we also showed the importance of water in drug–protein interactions. In addition, we reported the characteristics of the hydration pattern and the dynamic distance distribution around the interesting residues. The results indicated that Asp318 plays the role of a general base that can activate water molecule for nucleophilic attack on cAMP. As expected, His160 plays the role of a proton donor for cAMP.