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Pin1 is an enzyme that specificallycatalyzes the cis–transisomerization of prolineamide bonds in peptides that contain aphosphorylated threonine or serine residue in the position precedingproline. In the cell, the isomerization reaction is associated withcellular signaling and has been related to diseases such as Alzheimerand cancer. The catalytic mechanism by which Pin1 accelerates theisomerization reaction, however, is still unknown. In this study,we use molecular dynamics simulation in combination with the QM/MMmethodology to disclose the influence of the residues Ser-154 andCys-113 in the enzyme and the phosphorylated threonine residue inthe peptide on the reaction mechanism. To account for the correctelectrostatic interaction between the three residues and the reactivecenter, we derive atomic charges that account for the varying electrostaticfield in the catalytic cavity. Different methods based on reproducingthe molecular electrostatic potential or an atoms in molecules approachwere investigated. Finally, the reaction mechanism is analyzed withthe mean reaction force and the influence of the three residues isdisclosed. Our results show that Pin1 specifically catalyzes the isomerizationof the transconformer in a jump-rope type of motion,as suggested by us and confirmed experimentally by others. This isaccomplished by anchoring the threonine phosphate residue on one endof the peptide through electrostatic interactions with the basic triadof the enzyme and at the other end through specific enzyme–peptidehydrogen bonds. Cys-113 reduces the structural contribution to theactivation free energy through the stabilization of the cisconformer, and Ser-154 in combination with Gln-131 assist in theisomerization reaction of the transisomer. [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]

Carboxylation reactions represent a very special class of chemical reactions that is characterized by the presence of a carbon dioxide (CO2) molecule as reactive species within its global chemical equation. These reactions work as fundamental gear to accomplish the CO2 fixation and thus to build up more complex molecules through different technological and biochemical processes. In this context, a correct description of the CO2 electronic structure turns out to be crucial to study the chemical and electronic properties associated with this kind of reactions. Here, a systematic study of CO2 electronic structure and its contribution to different carboxylation reaction electronic energies has been carried out by means of several high‐level ab initio post‐Hartree Fock (post‐HF) and density functional theory (DFT) calculations for a set of biochemistry and inorganic systems. We have found that for a correct description of the CO2 electronic correlation energy it is necessary to include post‐CCSD(T) contributions (beyond the gold standard). These high‐order excitations are required to properly describe the interactions of the four π‐electrons associated with the two degenerated π‐molecular orbitals of the CO2 molecule. Likewise, our results show that in some reactions it is possible to obtain accurate reaction electronic energy values with computationally less demanding methods when the error in the electronic correlation energy compensates between reactants and products. Furthermore, the provided post‐HF reference values allowed to validating different DFT exchange‐correlation functionals combined with different basis sets for chemical reactions that are relevant in biochemical CO2 fixing enzymes. © 2019 Wiley Periodicals, Inc. Schematic representation of the electronic correlation energy for reactants and products in two representative carboxylation reactions. The height of each box represents the total electronic correlation energy calculated at CBS limit and the respective color shows the amount recovered by a specific electronic structure method. Errors in the calculated reaction energies are much larger when no error compensation between reactants and products takes place. [ABSTRACT FROM AUTHOR]