Abstract
We discuss problems related to in silico studies of enzymes and show that accurate and converged free energy changes for complex chemical reactions can be computed if a method based on a thermodynamic cycle is employed. The method combines the sampling speed of molecular mechanics with the accuracy of a high-level quantum mechanics method. We use the method to compute the free energy barrier for a methyl transfer reaction catalyzed by the enzyme catechol O-methyltransferase at the level of density functional theory. The surrounding protein and solvent are found to have a profound effect on the reaction, and we show that energies can be extrapolated easily from one basis set and exchange-correlation functional to another. Using this procedure we calculate a barrier of 69 kJ/mol, in excellent agreement with the experimental value of 75 kJ/mol.
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