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Dynamic structures of phosphodiesterase‐5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations

Various quantum mechanical/molecular mechanical (QM/MM) geometry optimizations starting from an x‐ray crystal structure and from the snapshot structures of constrained molecular dynamics (MD) simulations have been performed to characterize two dynamically stable active site structures of phosphodiesterase‐5 (PDE5) in solution. The only difference between the two PDE5 structures exists in the catalytic, second bridging ligand (BL2) which is HO− or H2O. It has been shown that, whereas BL2 (i.e. HO−) in the PDE5(BL2 = HO−) structure can really bridge the two positively charged metal ions (Zn2+ and Mg2+), BL2 (i.e. H2O) in the PDE5(BL2 = H2O) structure can only coordinate Mg2+. It has been demonstrated that the results of the QM/MM geometry optimizations are remarkably affected by the solvent water molecules, the dynamics of the protein environment, and the electronic embedding charges of the MM region in the QM part of the QMM/MM calculation. The PDE5(BL2 = H2O) geometries optimized by using the QM/MM method in different ways show strong couplings between these important factors. It is interesting to note that the PDE5(BL2 = HO‐) and PDE5(BL2 = H2O) geometries determined by the QM/MM calculations neglecting these three factors are all consistent with the corresponding geometries determined by the QM/MM calculations that account for all of these three factors. These results suggest the overall effects of these three important factors on the optimized geometries can roughly cancel out. However, the QM/MM calculations that only account for some of these factors could lead to considerably different geometries. These results might be useful also in guiding future QM/MM geometry optimizations on other enzymes. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008