Joaquín Ortega-Castro

DFT Studies on Schiff Base Formation of Vitamin B6 Analogues. Reaction between a Pyridoxamine-Analogue and Carbonyl Compounds

A comprehensive theoretical study based on density functional theory calculations (B3LYP and M06-2X functionals) of the formation of Schiff bases of pyridoxamine analogues with two different aldehydes was conducted. The reaction mechanism was found to involve two steps, namely: (1) formation of a carbinolamine and (2) dehydration of the carbinolamine to give the final imine. Also, consistent with available experimental evidence, the carbinolamine dehydration was the rate-determining step of the process determined by means of M06-2X functional. Using an appropriate solvation method and reactant conformation ensures that all proton transfers involved will be intramolecular, which substantially reduces energy barriers and facilitates reaction in all cases. The formation of a Schiff base between pyridoxal 5-phosphate (PLP) and an amine or amino acid requires the contribution of an external water molecule in order to facilitate proton transfers. On the other hand, the formation of a Schiff base between pyridoxamine 5-phosphate (PMP) and a carbonyl compound requires no external aid since the spatial arrangement of the functional groups in PMP ensures that all proton transfers will be intramolecular.

Density functional theory and Monte Carlo study of octahedral cation ordering of Al/Fe/Mg cations in dioctahedral 2:1 phyllosilicates

Abstract The ordering of octahedral Al3+, Fe3+, and Mg2+ cations in dioctahedral 2:1 phyllosilicates was studied theoretically. Quantum mechanical calculations based on density functional theory (DFT) were performed for optimizing different cation distributions along the octahedral sheet. Three systems of two species (Al3+/Mg2+, Al3+/Fe3+, and Fe3+/Mg2+) were studied to obtain the cation exchange potentials Jn as first, second, third, and fourth nearest neighbors. Monte Carlo (MC) simulations based on the previously calculated cation exchange potentials Jn of these binary systems showed ordering phase transition in the distribution of the octahedral cations, with different ordering patterns. Ordered phases are depending on composition and on third and fourth neighbor range interactions. The effect of hydrostatic pressure can affect the cation ordering of the octahedral sheet. The two-species model was extended to a three-species ordering MC simulation model. In our case, we do not find perfect long-range ordering in the three-species systems. Instead we find some domains with different ordering patterns.

Theoretical calculations of stability constants and pKa values of metal complexes in solution: application to pyridoxamine–copper(II) complexes and their biological implications in AGE inhibition

Accurate prediction of thermodynamic constants of chemical reactions in solution is one of the current challenges in computational chemistry. We report a scheme for predicting stability constants (log β) and pKa values of metal complexes in solution by means of calculating free energies of ligand- and proton-exchange reactions using Density Functional Theory calculations in combination with a continuum solvent model. The accuracy of the predicted log β and pKa values (mean absolute deviations of 1.4 and 0.2 units respectively) is equivalent to the experimental uncertainties. This theoretical methodology provides direct knowledge of log β and pKa values of major and minor species, so it is of potential use in combination with experimental techniques to obtain a detailed description of the microscopic equilibria. In particular, the proposed methodology is shown to be especially useful for obtaining the real acidity constants of those chelates where the metal-ligand coordination changes as a result of ligand deprotonation. The stability and acidity constants of pyridoxamine-Cu(2+) chelates calculated with the proposed methodology show that pyridoxamine is an efficient scavenging agent of Cu(2+) under physiological pH conditions. This is of special interest as Cu(2+) overload is involved in the formation of advanced glycation end-products (AGEs) and their associated degenerative medical conditions.

High-pressure behavior of 2M1 muscovite

Abstract The crystal structure and pressure influence (between 0-6 GPa) on 2M1 muscovite have been calculated by quantum-mechanical methods based on density functional theory (DFT) with optimized numerical LCAO basis sets and norm-conserving pseudopotentials. Tensions between 0.8 and 0 GPa have been also studied. Volumes as a function of pressure, computed from the generalized gradient approximation, are closer to the experimental data than volumes calculated from the local density approximation. The crystal structure, bond distances, and main geometrical features agree with previous experimental values. A third-order Birch-Murnagham equation is fitted, giving a bulk modulus of 60.1 GPa, which reasonably agrees with the experimental data. Axis compressibilities are slightly smaller than those of the experimental data. The most compressible axis is the c axis. Bond strains, angles, the main geometrical features, and polyhedral strains are studied as a function of pressure, and these vary according to the experimental behavior. Tetrahedral and angles and corrugation show an oscillating behavior in the range of pressures used. The most important compressibilities are those related to the interlayer space, as it corresponds to the weakest bonding in the structure. The highest compressibility in the T-O-T layer along the [001] direction is determined by the octahedral sheet thickness. The compressibilities along the a and b axes are determined by the tetrahedra, as the most compressible polyhedra, and the α angle. Therefore, with our results the utility of periodic DFT methods for studying crystal structure and the effect of hydrostatic pressure on 2M1 muscovite are once again validated, and they are suitable to describe the compression of the crystal structure in detail.

Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study

We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC50 values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.

C−H Activation in Pyridoxal-5'-phosphate and Pyridoxamine-5'- phosphate Schiff Bases: Effect of Metal Chelation. A Computational Study

This study reports the carbon acidities of Cα and C4′ atoms in the Schiff bases of pyridoxal-5′-phosphate (PLP) and pyridoxamine-5′-phosphate (PMP) complexed with several biologically available metal ions (Mg2+, Ni2+, Zn2+, Cu2+, Al3+, and Fe3+). Density functional theory calculations were carried out to determine the free energies of proton exchange reactions of a set of 18 carbon acids and a Schiff base used as a reference species. The experimental pK(a) values of such carbon acids were used to calibrate the computed free energies in a range of 30 pK(a) units. Eventually, the pK(a)s of the chelates were obtained by calculating the corresponding free energies against the same reference species and by considering the previous calibration. The carbon acidity of Cα in the chelates of Mg2+, Ni2+, Zn2+, and Cu2+ varies between pK(a) 22 and pK(a) 13 whereas the pK(a) values of C4′ range between 18 and 7. Chelation of trivalent metals Al3+ and Fe3+ causes further decrease of the pK(a) values of Cα and C4′ down to 10 and 5, respectively. The results highlight the efficiency of the combined action of Schiff base formation and metal chelation to activate the Cα carbon of amino acids (pK(a) 29 for zwitterionic alanine). Our results explain that the experimental increase of transamination rates by Zn2+ chelation is due to stabilization of the reactive Schiff base species with respect to the free ligand under physiological pH conditions. However, the increase in reactivity for transamination due to Cu2+ and Al3+ chelation is mostly due to C–H ligand activation. Each metal ion activates the Cα and C4′ carbon atoms to a different extent, which can be exploited to favor specific reactions on the amino acids in aqueous solution. Metal chelation hinders both intramolecular and intermolecular proton-transfer reactions of the imino, phenol, and carboxylate groups. This is the only apparent inconvenience of metal complexes in enzymatic reactions, which, in turn, proposes their consideration for enzyme inhibition.

High- and low-spin Fe(III) complexes of various AGE inhibitors.

Density functional theory calculations [CPCM/UM06/6-31+G(d,p)] were used to elucidate the structures and relative stability of Fe(III) complexes with various ligands that inhibit the formation of advanced glycation end products (AGEs) or iron overloaded disease (viz. aminoguanidine, pyridoxamine, LR-74, Amadori compounds, and ascorbic acid). EDTA was used as the free energy reference ligand. The distorted neutral octahedral complex containing one iron atom and three molecules of pyridoxamine [Fe(PM)(3)] was found to be the most stable. The stability of the complexes decreases in the following chelate sequence: pyridoxamine, Amadori complex, aminoguanidine, LR inhibitor, and ascorbic acid.

Computational study of the elastic behavior of the 2M1 muscovite-paragonite series

Abstract Elastic properties are an important issue in explaining the behavior of seisms and to ascertain the mineralogical composition of the Earth’s shells through which seismic waves pass. Computational methods can yield an additional, detailed, free-of-heterogeneity model knowledge of the mineral series of interest. Therefore, a computational study on the influence of the interlayer cation in the muscovite-paragonite (Ms-Pg) series on the crystal cell, internal geometry, and the elastic properties was made to shed light on the mineralogical, geophysical, and geochemical properties of the series. These properties have been calculated by means of Density Functional Theory (SIESTA2.0.2 code). The crystal structure and internal geometry agreed with the range of experimental values in the literature. In general, elastic stiffness constants (EC) agreed with the known experimental values. ECs of different interlayer cation configurations for the middle concentration sample showed very similar values, except for C33, The majority of ECs, with the exception of C33 and C66, decreased as a function of Na′ [Na/(Na+K)], many of which showed ideal crystalline solution behavior, and some showed mixing terms. The polycrystalline bulk modulus registered similar values for the end-members of the series and a minimum at Na′ = 0.5, although an estimate of the value at room temperature made the Pg stiffer than Ms; while the shear modulus showed a decreasing trend as a function of the Na′. Velocities of the sound waves lowered as a function of Na′. Local deformabilities were also studied, where the highest deformability was found for the interlayer space. The results are discussed in the framework of the mineralogical, geochemical, and geophysical knowledge of the series.

A comparative DFT study of the Schiff base formation from acetaldehyde and butylamine, glycine and phosphatidylethanolamine

Mechanisms for the formation of the Schiff base from acetaldehyde and butylamine, glycine and phosphatidylethanolamine based on Dmol3/DFT calculations were realized. For the case of phosphatidylethanolamine, calculations were done under periodic boundary conditions, in an amine-phospholipid monolayer model with two molecules of phosphatidylethanolamine by cell. All models contained explicit aqueous solvent. In the three cases, a neutral amino group is used to model the nucleophilic attack on the carbonyl group of acetaldehyde, and water molecules form hydrogen bond networks. These networks were involved in the reactions by performing as proton-transfer carriers, important in some steps of reactions, and stabilizing reaction intermediates. In all the studied reactions, they take place in two steps, namely: (1) formation of a carbinolamine and (2) its dehydration to the Schiff base, being the dehydration the rate-determining step of the process, consistent with available experimental evidence for similar reactions. The main difference between the studied reactions is found in the value for relative free energy for the intermediates and transition states in the second step; these values are lower in the cases of glycine and phosphatidylethanolamine in comparison with butylamine, due the influence of their molecular environments. Based on the results, the aminophospholipid surface environment and carboxylic group of glycine may boost Schiff base formation via a neighboring catalyst effect.

Nonenzymatic Reactions above Phospholipid Surfaces of Biological Membranes: Reactivity of Phospholipids and Their Oxidation Derivatives

Phospholipids play multiple and essential roles in cells, as components of biological membranes. Although phospholipid bilayers provide the supporting matrix and surface for many enzymatic reactions, their inherent reactivity and possible catalytic role have not been highlighted. As other biomolecules, phospholipids are frequent targets of nonenzymatic modifications by reactive substances including oxidants and glycating agents which conduct to the formation of advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs). There are some theoretical studies about the mechanisms of reactions related to these processes on phosphatidylethanolamine surfaces, which hypothesize that cell membrane phospholipids surface environment could enhance some reactions through a catalyst effect. On the other hand, the phospholipid bilayers are susceptible to oxidative damage by oxidant agents as reactive oxygen species (ROS). Molecular dynamics simulations performed on phospholipid bilayers models, which include modified phospholipids by these reactions and subsequent reactions that conduct to formation of ALEs and AGEs, have revealed changes in the molecular interactions and biophysical properties of these bilayers as consequence of these reactions. Then, more studies are desirable which could correlate the biophysics of modified phospholipids with metabolism in processes such as aging and diseases such as diabetes, atherosclerosis, and Alzheimers disease.