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Abstract: The chorismate to prephenate enzyme catalyzed reaction has been used in this review as the conduit to show different theoretical approaches that have been used over the years in our laboratory to explain its molecular mechanism. This pericyclic reaction has the advantage that other protein scaffolds such as catalytic antibodies or some promiscuous enzymes present certain chorismate mutase activity. The obtained results on all these protein environments, by comparison with the uncatalyzed reaction in solution, have been used to propose, as a general conclusion, that the origin of enzyme catalysis is in the relative electrostatic stabilization of the transition state with respect to the Michaelis complex. This feature implies that reactants of catalyzed reaction were closer to the transition state than those of the non-catalyzed reaction. From this hypothesis, and considering the features of the wild type chorismate mutases as the optimal catalyst for the reaction, some mutations on both kinds of alternative proteins have been proposed which would presumably enhance the rate constant of the chemical step. The studies presented in this paper demonstrate that the improvements and developments of the methods and techniques of theoretical and computational chemistry are now mature enough to model physic-chemical properties of biological systems with good accuracy. The combination of a potent computational protocol with molecular engineering techniques can be a promising methodology to develop novel enzymes with new or more efficient catalytic functions.

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A conformational structures search of chorismate mutase substrate has been carried out using in vacuo AM1 and MP2/6-31G* methods and by means of a hybrid quantum mechanical/molecular mechanical (QM/MM) procedure in the solvated enzyme. Apart from the pseudodiequatorial and pseudodiaxial conformers of chorismate reported in the literature, new structures have been located using both methodologies. A comparative analysis of the results reveals the importance of the mechanical and electronic constraints imposed by the enzyme in this preequilibrium. These specific interactions between the substrate and the enzyme environment change the order of stability of the different conformers obtained in vacuo, thus stabilizing those structures that can be considered as the precursor for the rearrangement of chorismate to prephenate. The deformation energy of the enzyme to mold the substrate into the active site appears as the major factor in the energetic ordering of all the studied conformers.

Structural and vibrational properties of histamine monocation in aqueous solution have been studied by means Fourier transform vibrational spectroscopies and a continuum model with the B3PW91 functional. Solvent effects were incorporated by means of an ellipsoidal cavity model with a multipolar expansion (up to six order) of the solute's electrostatic potential. Calculations were always performed at the 6-31+G* ab initio level. Solutions in water and deuterium oxide were investigated. Discussion was focused on the trans N^τ−H conformer of histamine monocation, which is the predominant structure in water solution. The optimized geometry was compared to that reported for this species in the solid state by diffraction techniques, where the only conformer present is the trans N^τ−H. A general assignment was proposed for the infrared and Raman spectra of histamine monocation in solution, based on the isotopic shifts and a previous vibrational study in solid state. Force field and normal coordinate calculations were computed to support these assignments. The ab initio force constants were transformed into a set of locally symmetrized internal coordinates and subsequently scaled to the experimental frequencies by using one specific and two generic scaling factors. The comparison in terms of vibrational frequencies and normal coordinate descriptions supported most of the proposed assignments. The theoretical infrared spectra for the two isotopomers on the basis of the ab initio intensities also showed a good correlation with the experimental spectra. These results evidence that solute−solvent interactions must be explicitily taken into account in order to understand the vibrational behavior of polar species in solution; in addition, the use of multipolar expansions for the electrostatic potential together with a cavity adapted to the molecular shape improves significantly the performance of the solvation model.

Molecular dynamics simulations within the density functional−molecular mechanics approach are used to investigate amino acid chemistry in aqueous solution. Equilibrium solvation effects are studied in both the neutral and zwitterionic forms of the glycine. Dynamic solvent effects on amino acid reactions in water are illustrated through the simulation of the fast conversion of neutral glycine to its zwitterionic form. The different factors contributing to the intramolecular proton transfer are analyzed from a dynamic point of view.

A simulation of the lactate dehydrogenase (LDH) catalytic mechanism by means of the characterization of the global potential energy surface has been carried out by the PM3 quantum chemical method using a rather large model of the LDH active center. The minimum energy pathway for this process was established. The overall process is controlled by the hydride transfer from NADH towards pyruvate carbonyl carbon. The transition state structure that combines the hydride and proton transfers is obtained. There are two independent minima for products. In both minima the coenzyme rotation supplies the reversibility of the pyruvate-lactate interconversion. The results agree with recently published studies on transition state structure, kinetic isotope effects, and the hydride and proton transfers being coupled kinetically but not dynamically in the molecular mechanism of the LDH catalytic reaction.Copyright 1993, 1999 Academic Press

In this work we present a theoretical study of neutral and alkaline hydrolyses of N-methylazetidinone as a model of biological hydrolysis of β-lactam antibiotics. Calculations have been carried out at the HF and MP2 levels using the 3-21G, 6-31G*, and 6-31+G* basis sets. Solvent effects have been included by means of a polarizable continuum model. Our results indicate two possible reaction mechanisms for the β-lactam hydrolysis:  concerted and stepwise. In both the neutral and alkaline hydrolyses the concerted mechanism presents a free energy barrier lower than that of the stepwise mechanism.

The self-consistent reaction field (SCRF) theory was used to study structural and vibrational features of the amino acid l-glutamine in solution. Raman and infrared spectra of this molecule in solutions of H2O and D2O were recorded and measured. The bands were firstly assigned on the basis of the isotopic shifts. An ab initio quadratic force field at the 6-31+G* level was achieved. The calculation simulated a polar solvent by placing the molecule in an ellipsoidal cavity surrounded by a continuum dielectric. The theoretical results, in terms of structural parameters, vibrational frequencies and descriptions, and infrared intensities, were in satisfactory agreement with the experimental data.

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