T. Verstraelen

Pin1 is an enzyme that specifically catalyzes the cis–trans isomerization of proline amide bonds in peptides that contain a phosphorylated threonine or serine residue in the position preceding proline. In the cell, the isomerization reaction is associated with cellular signaling and has been related to diseases such as Alzheimer and cancer. The catalytic mechanism by which Pin1 accelerates the isomerization reaction, however, is still unknown. In this study, we use molecular dynamics simulation in combination with the QM/MM methodology to disclose the influence of the residues Ser-154 and Cys-113 in the enzyme and the phosphorylated threonine residue in the peptide on the reaction mechanism. To account for the correct electrostatic interaction between the three residues and the reactive center, we derive atomic charges that account for the varying electrostatic field in the catalytic cavity. Different methods based on reproducing the molecular electrostatic potential or an atoms in molecules approach were investigated. Finally, the reaction mechanism is analyzed with the mean reaction force and the influence of the three residues is disclosed. Our results show that Pin1 specifically catalyzes the isomerization of the trans conformer in a jump-rope type of motion, as suggested by us and confirmed experimentally by others. This is accomplished by anchoring the threonine phosphate residue on one end of the peptide through electrostatic interactions with the basic triad of the enzyme and at the other end through specific enzyme–peptide hydrogen bonds. Cys-113 reduces the structural contribution to the activation free energy through the stabilization of the cis conformer, and Ser-154 in combination with Gln-131 assist in the isomerization reaction of the trans isomer.

We present a systematic theoretical study on the dissociation of diatomic molecules and their spectroscopic constants using our recently presented geminal-based wave function ansätze. Specifically, the performance of the antisymmetric product of rank two geminals (APr2G), the antisymmetric product of 1-reference-orbital geminals (AP1roG) and its orbital-optimized variant (OO-AP1roG) are assessed against standard quantum chemistry methods. Our study indicates that these new geminal-based approaches provide a cheap, robust, and accurate alternative for the description of bond-breaking processes in closed-shell systems requiring only mean-field-like computational cost. In particular, the spectroscopic constants obtained from OO-AP1roG are in very good agreement with reference theoretical and experimental data.

The electronegativity equalization method is classically used as a method allowing the fast generation of atomic charges using a set of calibrated parameters and provided knowledge of the molecular structure. Recently, it has started being used for the calculation of other reactivity descriptors and for the development of polarizable and reactive force fields. For such applications, it is of interest to know whether the method, through the inclusion of the molecular geometry in the Taylor expansion of the energy, would also allow sufficiently accurate predictions of spectroscopic data. In this work, relevant quantities for IR spectroscopy are considered, namely the dipole derivatives and the Cartesian Hessian. Despite careful calibration of parameters for this specific task, it is shown that the current models yield insufficiently accurate results.