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.