Quantum mechanical/molecular mechanical (QM/MM) geometry optimizations of the X-ray crystal structures of PDE10-AMP (PDB code 2OUN) and PDE10-GMP (PDB code 2OUQ) complexes have been performed to characterize the state of the AMP and GMP products, respectively. Results show that only one phosphate oxygen atom (OI) is protonated for both AMP and GMP product complexes. In addition, QM/MM calculations have resolved the orientation of the amide group of Gln726 in PDE10-GMP which was in conflict with the assignment of the guanine group of GMP in the X-ray crystal structure. Calculations reveal that the amide oxygen and nitrogen atom of Gln726 are rotated 180 degrees, resulting in two strong hydrogen bonds formed between the amide group of Gln726 and the guanine group of GMP. Binding free energy calculations for both QM/MM-optimized structures confirm the new conformational assignment of Gln726 in PDE10-GMP. The calculated binding free energy of the rotated structure is similar to 22 kcal/mol lower than the X-ray crystal assignment. The lower energy is mainly derived from the formation of two hydrogen bonds between the amide group of Gln726 and the guanine group of GMP. This implies that the orientation of the amide oxygen and nitrogen atoms in PDE10-AMP is different from PDE10-GMP. Finally, our results help to understand why PDE10 can hydrolyze both cAMP and cGMP.