ONIOM quantum chemistry study of cyclic nucleotide recognition in phosphodiesterase 5

摘要

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that contribute to the regulation of cyclic nucleotides in the cell by catalyzing the hydrolysis reaction of the 03'-phosphorous bond, yielding the noncyclic nucleotide as the product. The principal substrates are cyclic 3',5'-adenosine and -guanosine monophosphate (cAMP and cGMP). PDE5, an important target of drug inhibition, is known to be highly selective for hydrolysis of cGMP. We use all-quantum hybrid calculations to accurately describe the binding interactions between PDE5 and cAMP/cGMP for the first time. The main reasons for cGMP preference in PDE5 are found to be to the fixed orientation of a conserved glutamine residue (Gln 817) together with the fixed orientation of a nonconserved glutamine residue (Gln 775). We report ONIOM(B3LYP/6-31g(d):PM3MM) binding energies, which reflect favorable guanine alignment with Gln 817 and steric crowding of adenine by Gln 775. (c) 2007 Wiley Periodicals.