How Does Pin1 Catalyze
the Cis–Trans Prolyl
Peptide Bond Isomerization? A QM/MM and Mean Reaction Force Study
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Abstract
Pin1 represents an enzyme that specifically catalyzes
the isomerization
of peptide bonds between phosphorylated threonine or serine residues
and proline. Despite its relevance as molecular timer in a number
of biological processes related to cancer and Alzheimer disease, a
detailed understanding of the factors contributing to the catalysis
is still missing. In this study, we employ extensive QM/MM molecular
dynamics simulations in combination with the mean reaction force (MRF)
to discern the influence of the enzyme on the reaction mechanism and
the origin of the catalysis. As a recently introduced method, the
MRF separates the activation free energy barrier to reach the transition
state into structural and electronic contributions providing a more
detailed description of the enzyme’s function. As a reference,
we first study the isomerization starting from the cis form in solution
and obtain a free energy barrier and a reaction free energy, which
are in agreement with previous studies and experiment. With the new
mean reaction force method, intramolecular hydrogen bonds in the peptide
were identified that stabilize the transition state and reduce the
electronic contribution to the free energy barrier. To elucidate the
mechanism of catalysis of Pin1, the reaction in solution and in the
catalytic cavity of the enzyme were compared. Both yield the same
free energy barrier for the isomerization of the cis form, but with
different decomposition in structural and electronic contributions
by the mean reaction force. The enzyme reduces the energy required
for structural rearrangements to reach the transition state, pointing
to a destabilization of the reactant, but increases the electronic
contribution to the barrier through specific enzyme–peptide
hydrogen bonds. In the reverse reaction, the isomerization of the
trans form, the enzyme alters the energetics and the mechanism of
the reaction considerably. Unfavorable enzyme–peptide interactions
in the catalytic cavity during the isomerization change the reaction
coordinate, resulting in two minima with small energy differences
to the transition state. These small free energy barriers should in
principle make the reaction feasible at room temperature once the
conformer is bound in the right conformation