ONIOM quantum chemistry study of cyclic nucleotide recognition in phosphodiesterase 5

AbstractCyclic nucleotide phosphodiesterases (PDEs) are enzymes that contribute to the regulation of cyclic nucleotides in the cell by catalyzing the hydrolysis reaction of the O3′‐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. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007