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Pin1 represents an enzyme that specifically catalyzesthe isomerizationof peptide bonds between phosphorylated threonine or serine residuesand proline. Despite its relevance as molecular timer in a numberof biological processes related to cancer and Alzheimer disease, adetailed understanding of the factors contributing to the catalysisis still missing. In this study, we employ extensive QM/MM moleculardynamics simulations in combination with the mean reaction force (MRF)to discern the influence of the enzyme on the reaction mechanism andthe origin of the catalysis. As a recently introduced method, theMRF separates the activation free energy barrier to reach the transitionstate into structural and electronic contributions providing a moredetailed description of the enzyme’s function. As a reference,we first study the isomerization starting from the cis form in solutionand obtain a free energy barrier and a reaction free energy, whichare in agreement with previous studies and experiment. With the newmean reaction force method, intramolecular hydrogen bonds in the peptidewere identified that stabilize the transition state and reduce theelectronic contribution to the free energy barrier. To elucidate themechanism of catalysis of Pin1, the reaction in solution and in thecatalytic cavity of the enzyme were compared. Both yield the samefree energy barrier for the isomerization of the cis form, but withdifferent decomposition in structural and electronic contributionsby the mean reaction force. The enzyme reduces the energy requiredfor structural rearrangements to reach the transition state, pointingto a destabilization of the reactant, but increases the electroniccontribution to the barrier through specific enzyme–peptidehydrogen bonds. In the reverse reaction, the isomerization of thetrans form, the enzyme alters the energetics and the mechanism ofthe reaction considerably. Unfavorable enzyme–peptide interactionsin the catalytic cavity during the isomerization change the reactioncoordinate, resulting in two minima with small energy differencesto the transition state. These small free energy barriers should inprinciple make the reaction feasible at room temperature once theconformer is bound in the right conformation. [ABSTRACT FROM AUTHOR]