QM−FE and Molecular Dynamics Calculations on Catechol O-Methyltransferase: Free Energy of Activation in the Enzyme and in Aqueous Solution and Regioselectivity of the Enzyme-Catalyzed Reaction

摘要: We present combined quantum mechanical and free energy (QM−FE) as well molecular dynamics (MD) calculations to investigate the methyl transfer reaction catalyzed by enzyme catechol O-methyltransferase (COMT). The calculated transition state energy, ΔG‡, of 24.5 kcal/mol for enzymatic is in reasonable agreement with experiment (18 kcal/mol), level improves when substrates are allowed slightly deviate from their minimized interpolated geometries. ΔG‡ water 5 higher than that found cratic terms not considered, this difference increases 14−18 they included, very good estimated rate enhancement due catalysis 1011 (corresponding ΔΔG‡ ≈ 15 kcal/mol). In contrast trypsin, studied earlier QM−FE methods, gas phase significantly lower observed or i...