We present a new more general way to combine ab initio
quantum mechanical calculations with
classical mechanical free energy perturbation approach to calculate the
energetics of enzyme-catalyzed reactions
and the same reaction in solution. This approach, which enables
enzyme and solution reactions to be compared
without the use of empirical parameters, is applied to the formation of
the tetrahedral intermediate in trypsin,
but it should be generally applicable to any enzymatic reaction.
Critical to the accurate calculation of the
reaction energetics in solution is the estimate of the free energy to
assemble the reacting groups, where the
approach recently published by Hermans and Wang (J. Am. Chem.
Soc.
1997, 119, 2707) was used.
A central
aspect of this new approach is the use of the RESP protocol to
calculate the charge distribution of structures
along the reaction pathway, which enables us to circumvent problems in
partitioning the charge across a residue
that is being divided into QM and MM parts. The classical
mechanical free energy calculations are implemented
with two different approaches, “Cartesian mapping” and “flexible
FEP”. The similarity of the results found
by using these two approaches supports the robustness of the calculated
free energies. The calculated free
energies are in quite good agreement with available experimental data
for the activation free energies in the
enzyme and aqueous phase reactions.
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