Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic nucleotide phosphodiesterases (PDEs) constitute a large superfamily of enzymes regulating concentrations of intracellular second messengers cAMP and cGMP through PDE-catalyzed hydrolysis. Although three-dimensional x-ray crystal structures of PDE4 and PDE5 have been reported, it is uncertain whether a critical, second bridging ligand (BL2) in the active site is H2O or HO- because hydrogen atoms cannot be determined by x-ray diffraction. The identity of BL2 is theoretically determined by performing molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations, for the first time, on the protein structures resolved by x-ray diffraction. The computational results confirm our previous suggestion, which was based on QM calculations on a simplified active site model, that BL2 in PDE4 should be HO-, rather than H2O, serving as the nucleophile to initialize the catalytic hydrolysis of cAMP. The molecular dynamics simulations and QM/MM calculations on PDE5 demonstrate for the first time that the BL2 in PDE5 should also be HO- rather than H2O as proposed in recently published reports on the x-ray crystal structures, which serves as the nucleophile to initialize the PDE5-catalyzed hydrolysis of cGMP. These fundamental structural insights provide a rational basis for future structure-based drug design targeting PDEs.
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PMID:Characterization of a catalytic ligand bridging metal ions in phosphodiesterases 4 and 5 by molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations. 1691 14

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.
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PMID:Dynamic structures of phosphodiesterase-5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations. 1816 87