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The mean reaction force is introduced as the negative derivative of the free energy along a predefined reaction path. In analogy to the reaction force, this descriptor allows detailed characterization of different processes of the reaction mechanism and the assignment of electronic and structural free energy contributions to activation barriers. Due to its free energy dependence, the mean reaction force represents a new tool to study the influence of the environment on the reaction mechanism. Moreover, it enables the separation of catalytic effects in structural and electronic components responsible for the free energy barrier reduction of a reaction. To validate the method, the intramolecular proton transfer in tryptophan was studied in the gas phase, in aqueous solution and at the vacuum-water interface employing molecular dynamics simulation in combination with ab initio calculations and the quantum molecular/molecular mechanics (QM/MM) methodology. The obtained results were compared to static vacuum and continuum calculations. The mean reaction force distinguishes structural rearrangements as the dominant free energy component to reach the transition state from the neutral form, whereas electronic reorganization predominates the activation of the zwitterion in aqueous solution. In addition, it identifies the origin of the reduction of the activation barrier for desolvated functional groups at the water-vacuum interface as the absence of hydrogen bonds which stabilize charge delocalized species. [ABSTRACT FROM AUTHOR]

Conformational changes in enzymes and their role in their catalytic activity have been thoroughly addressed experimentally and theoretically. There is a vivid discussion in the field of enzyme catalysis on whether conformational changes of the enzyme are coupled to catalysis, or whether transition state stabilization through the preorganized protein and its electrostatic properties govern the catalysis. In this study, an additional contribution to the catalysis of one specific enzyme, Pin1, is proposed, which arises from its conformational selection of the peptide substrate from aqueous solution with the lowest activation barrier. The most stable conformers of the reactant (cis) and product (trans) peptide were identified through molecular dynamics simulations in combination with metadynamics. The cis-trans isomerization reaction was studied with quantum mechanical/molecular mechanical molecular dynamics simulations and density functional theory together with the mean reaction force, which allows us to separate structural and electronic contributions to the activation barrier. Our results show that enzyme Pin1 binds the trans isomer in the conformation of the peptide with the smallest activation barrier and reduces the barrier further through specific substrate-enzyme interactions, as we have shown previously. The activation barrier of the cis peptide is independent of the conformer and remains unchanged in the enzyme. [ABSTRACT FROM AUTHOR]

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]