The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations: Applications to Enzymatic Reactions.
In this chapter, we discuss the influence of an anisotropic protein environment on the reaction mechanisms of saccharopine reductase and uroporphyrinogen decarboxylase, respectively, via the use of a quantum mechanical and molecular mechanical (QM/MM) approach. In addition, we discuss the importance of selecting a suitable DFT functional to be used in a QM/MM study of a key intermediate in the mechanism of 8R-lipoxygenase, a nonheme iron enzyme. In the case of saccharopine reductase, while the enzyme utilizes a substrate-assisted catalytic pathway, it was found that only through treating the polarizing effect of the active site, via the use of an electronic embedding formalism, was agreement with experimental kinetic data obtained. Similarly, in the case of uroporphyrinogen decarboxylase, the effect of the protein environment on the catalytic mechanism was found to be such that the calculated rate-limiting barrier is in good agreement with related experimentally determined values for the first decarboxylation of the substrate. For 8R-lipoxygenase, it was found that the geometries and energies of the multicentered open-shell intermediate complexes formed during the mechanism are quite sensitive to the choice of the density functional theory method. Thus, while density functional theory has become the method of choice in QM/MM studies, care must be taken in the selection of a particular high-level method.
['Bushnell|Eric André C|EA|', 'Berryman|Victoria Erica J|VE|', 'Gauld|James W|JW|', 'Boyd|Russell J|RJ|']
D000818:Animals D016880:Anisotropy D037421:Anthozoa D001091:Arachidonate Lipoxygenases D020134:Catalytic Domain D006801:Humans D007700:Kinetics D056004:Molecular Dynamics Simulation D011789:Quantum Theory D012443:Saccharopine Dehydrogenases D013379:Substrate Specificity D013816:Thermodynamics D014575:Uroporphyrinogen Decarboxylase
Protein environment Saccharopine reductase Uroporphyrinogen decarboxylase Computational enzymology Lipoxygenase Multicentered open shell Quantum mechanics/molecular mechanics