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O Tapia

Publications and source records attributed to O Tapia.

At least 19 recordsLinked to original sources
PubMed2005

Exploring two-state reactivity pathways in the cycloaddition reactions of triplet methylene.

Spin forbidden 1,2-cycloadditions of triplet methylene to alkenes have been theoretically studied as an example of the two-state reactivity paradigm in organic chemistry. The cycloadditions of triplet methylene to ethylene and the (E)- and (Z)-2-butene isomers show spin inversion after the transition state and therefore with no effect on the reaction rate. A local analysis shows that while triplet methylene addition to alkenes leading to the formation of a biradical intermediate is driven by spin polarization, the ring closure step to yield cyclopropane is a pericyclic process. We have found that at the regions in the potential energy surface where the spin crossover is likely to occur, the spin potential in the direction of increasing spin multiplicity, mu(+)(s), tends to equalize the one in the direction of decreasing spin multiplicity, mu(-)(s). This equalization facilitates the spin transfer process driven by changes in the spin density of the system.

Journal Article↗
PubMed2005

Pharmacokinetics and synovial fluid concentrations of flurbiprofen enantiomers in horses: chiral inversion.

Flurbirpofen (FBP), a member of the 2-aryl propionate nonsteroidal anti-inflammatory drug class, has potent anti-inflammatory and analgesic properties. The commercial preparation is a racemic mixture of the R(-) and S(+) enantiomers of FBP. In this study, R(-) and S(+) FBP were used to investigate the metabolic chiral inversion. Each enantiomer was administered separately (0.25 mg/kg) and in a racemic mixture (0.5 mg/kg) intravenously to horses. Plasma and synovial concentration of each enantiomer was determined and the disposition of each was analyzed. After intravenous administration of R(-) FBP and S(+) FBP to horses no chiral inversion was detected. After the administration of the FBP racemate and individual enantiomers no differences were observed between pharmacokinetic parameters [t(1/2beta) (h), Cl (L/h.kg), AUC (microg.h/mL), Vss (L/kg) and MRT (h)] for R(-) and S(+) FBF. Synovial fluid concentrations of both FBP enantiomers were lower than plasma concentrations and no stereoselective differences were detected. These data indicate that the disposition of FBF in horses is not enantioselective and demonstrate a difference in the pharmacokinetic behavior of the enantiomers as compared with other 2-aryl-propionic acids, such as carprofen, ketoprofen and vedaprofen in the horse.

Animals↗
PubMed2005

The chemotherapy of chagas' disease: an overview.

The review presents: a) a brief description of the disease; b) a summary of the most important metabolic targets so far identified in Trypanosome cruzi (T. cruzi) along with corresponding inhibitor compounds; c) the current state of knowledge on the trypanothione reductase system of trypanosomatids with reference to oxidative stress defenses; d) detailed discussions on T. cruzi trypanothione reductase inhibitors such as nitrofuranes, naphthoquinones and phenothiazines. As yet, the chemotherapy of Chagas' disease remains an unsolved problem. Further search for new drugs must continue by means of nucleating existing chemotherapy efforts.

Animals↗
PubMed2002

Chiral inversion of (R)-(-)-fenoprofen in guinea-pigs pretreated with clofibrate.

The influence of clofibrate on the stereoconversion of fenoprofen (FPF) was studied in guinea pigs. This hypolipidaemic agent has been related to some biochemical changes in the liver leading to an increase in the chiral inversion process. Two groups of animals (n = 6 per group) were pretreated with oral doses of clofibrate (280 mg/kg per day) for three days and were then given (R)- or (S)-FPF (5 mg/kg, IV). The FPF enantiomers were extracted from the guinea-pigs' plasma using a solid phase procedure and analysed by HPLC with previous derivatization with L-leucinamide. Pretreatment with clofibrate increased the chiral inversion of (R)-FPF in favour of the pharmacologically active (S)-FPF enantiomer. Before this metabolic interaction can be applied to therapy with fenoprofen, the toxic effects of (S)-(+)-FPF on the gastrointestinal and renal tracts and the interference by (R)-(-)-FPF with the metabolism of lipids should be thoroughly evaluated.

Animals↗
PubMed2001

Structural transitions in neutral and charged proteins in vacuo.

In vacuo proteins provide a simple laboratory to explore the roles of sequence, temperature, charge state, and initial configuration in protein folding. Moreover, by the very absence of solvent, the study of anhydrous proteins in vacuo will also help us to understand specific environmental effects. From the experimental viewpoint, these systems are now beginning to be characterized at low resolution. Molecular dynamics (MD) simulations, in combination with tools for protein shape analysis, can complement experiments and provide further insights on the folding-unfolding transitions of these proteins. We review some aspects of this issue by using the results from a detailed MD study of hen egg-white lysozyme. For lysozyme ions, unfolding can be triggered by Coulombic repulsion. In neutral lysozyme, unfolding can be induced by centrifugal forces and also by weakening the monomer-monomer interaction. In both cases, the resulting unfolded transients can be used as initial configurations for relaxation dynamics. All trajectories are analyzed in terms of global molecular shape features of the backbone, including its anisometry and chain entanglement complexity. This strategy allows us to quantify separately the degree of polymer collapse and the evolution of large-scale folding features. Using these last two notions, we discuss some basic questions regarding the nature of the accessible paths associated with unfolding from, and refolding into, compact conformers.

Animals↗
PubMed2000

Chiral inversion of R(-) fenoprofen and ketoprofen enantiomers in cats.

The chiral inversion process is a characteristic metabolic pathway for different aryl-2-propionic acids or profens. Important variations have been observed between these individual compounds as well as between animal species. In this study, R(-) fenoprofen [R(-)FPF] and R(-) ketoprofen [R(-) KTF] were used to investigate their comparative stereoconversion in cats. After intravenous (i.v.) administration of R(-) FPF, the percentage of chiral inversion was 93.20+/-13.70%. A highly significant correlation (r: 0.978) was observed between the clearance of R(-) FPF and the chiral inversion process. After i.v. administration of R(-) KTF, the percentage of inversion was only 36.73+/-2.8%. No correlation between the clearance of R(-) KTF and this process was observed. R(-) FPF was metabolized by the pathways of thioesterification - chiral inversion processes. For R(-) KTF, the competitive metabolic pathways, glucuronidation and hydroxylation may be involved. However, these metabolic steps are saturable or less functional in cats. Moreover, the thioesterification of R(-) KTF in in vitro studies has been shown to be important in carnivores. The lack of correlation between clearance and chiral inversion process of R(-) KTF may be finally explained by deviation of thioesterification to other metabolic pathways of lipids and/or aminoacid conjugation, particulary glicine derivatives.

Animals↗
PubMed1999

Unfolded in vacuo lysozyme folds into native, quasinative, and compact structures.

We show that the relaxation dynamics of unfolded in vacuo lysozyme is not random. Analyses of molecular dynamics trajectories in a convenient space of molecular shape descriptors reveal a "favored" pattern of transitions leading to stable conformations. The relaxation paths exhibit a balanced change in shape features: globular spheroids are formed slowly enough to allow the proper entanglement of secondary-structural elements. The present study shows that a protein in vacuo can actually (re)fold into native and quasinative structures. The driving force for these transformations is intrinsic to the polypeptide chain.

Chemical Phenomena↗
PubMed1999

Proteins in vacuo: a molecular dynamics study of the unfolding behavior of highly charged disulfide-bond-intact lysozyme subjected to a temperature pulse.

Molecular dynamics simulations were used to interpret a variety of experimental data on highly charged disulfide-bond-intact lysozyme in vacuo. The simulation approach involved submitting a model of the protein [Reimann, Velázquez, and Tapia, J. Phys. Chem. B 102, 9344 (1998)] in a given charge state to a 3-ns-long heat pulse (usually at 500 K) followed by cooling or relaxation for 1 ns back to room temperature (293 K). This treatment yielded a charge threshold around Q(0)=8+ for obtaining significant unfolding, as indicated by an enhancement in collision cross section and conformer length. The collision cross sections and lengths theoretically obtained, along with the threshold charge state for initiating unfolding, were compatible with experimental results on lysozyme in vacuo. The unfolded, highly elongated conformations obtained for Q> or = 9+ displayed a significant level of non-native beta-sheet content which appeared to be additionally stabilized by charge self-solvation.

Animals↗
PubMed1998

Modelling a 3D structure for EgDf1 from Echinococcus granulosus: putative epitopes, phosphorylation motifs and ligand.

EgDf1 is a developmentally regulated protein from the parasite Echinococcus granulosus related to a family of hydrophobic ligand binding proteins. This protein could play a crucial role during the parasite life cycle development since this organism is unable to synthetize most of their own lipids de novo. Furthermore, it has been shown that two related protein from other parasitic platyhelminths (Fh15 from Fasciola hepatica and Sm14 from Schistosoma mansoni) are able to confer protective inmunity against experimental infection in animal models. A three-dimensional structure would help establishing structure/function relationships on a knowledge based manner. 3D structures for EgDf1 protein were modelled by using myelin P2 (mP2) and intestine fatty acid binding protein (I-FABP) as templates. Molecular dynamics techniques were used to validate the models. Template mP2 yielded the best 3D structure for EgDf1. Palmitic and oleic acids were docked inside EgDf1. The present theoretical results suggest definite location in the secondary structure of the epitopic regions, consensus phosphorylation motifs and oleic acid as a good ligand candidate to EgDf1. This protein might well be involved in the process of supplying hydrophobic metabolites for membrane biosynthesis and for signaling pathways.

Amino Acid Sequence↗
PubMed1998

DNA structure and fluctuations sensed from a 1.1ns molecular dynamics trajectory of a fully charged Zif268-DNA complex in water.

Molecular dynamics simulations of the zinc finger domain of protein Zif268, in a complex with a high affinity DNA sequence, yields a globally stable system with small yet significant readjustments with persistence time of the order of 1.1ns. The results confirm the quality of the standard GROMOS87 force field with a corrected solvent-to-solute interaction that does not affect the water-water SPC interactions nor the intra-molecular cohesive forces. Specificity determinants are discussed. The simulations of DNA alone, with the same force field, showed the important role played by the solvent and the symmetry of the counterion distribution. (Tapia & Velázquez, J. Am. Chem. Soc., 119, 5934, 1997) In the present work, this feature was retained when appropriate. The results for root mean square deviations and temperature B-factors illustrate the reliability of this approach. The structure of DNA is held by its interactions with the zinc finger protein. This behavior is not much affected by the slow whithering away of finger-1 from DNA. The factors contributing to the molecular stability found in GROMOS' potential energy function appear to be sufficient to yield stable fluctuation patterns when surrounding medium effects are properly included.

Computer Simulation↗
PubMed1996

On the sensitivity of MD trajectories to changes in water-protein interaction parameters: the potato carboxypeptidase inhibitor in water as a test case for the GROMOS force field.

A critical evaluation is presented of the sensitivity of the results of molecular dynamics simulations of proteins to changes in the parameters describing water-protein and protein-protein van der Waals interactions in the GROMOS force field. The origin of the van der Waals and electrostatic parameters of the GROMOS standard force field is reviewed, and possible weaknesses are discussed. Four alternate sets of van der Waals parameters for the oxygen types of the GROMOS force field that have been suggested by different authors are then tested against the original force field. Six 500 ps molecular dynamics simulations of the potato carboxypeptidase inhibitor (PCI) in solution using the different parameter sets are analyzed and the results compared with the available X-ray and NMR data. It is shown that the behavior of the molecular system is very sensitive to changes in the van der Waals parameters of the oxygens, especially when affecting the interactions between water and aliphatic or aromatic groups. It is also shown that correction of just the repulsive van der Waals parameter of the water oxygen for its interactions with nonpolar groups is sufficient to correct the main deficiency of the original GROMOS parameter set. Nevertheless, the present study suggest that further refinement of the current parameters is still needed for a proper representation of nonbonded interactions.

Algorithms↗
PubMed1995

L3 loop-mediated mechanisms of pore closing in porin: a molecular dynamics perturbation approach.

L3 loop-mediated mechanisms for pore closing in porin are investigated with molecular dynamics simulation, using an approach that can be related to the phenomenon of voltage gating. Voltage gating is seen as a perturbation of the electrostatic screening inside the porin pore where, by the influence of the potential gradient, water and counter-ion distribution can be slightly displaced from their equilibrium distribution. This is simulated by perturbing the screening electrostatics of ionizable groups inside the pore. Under these conditions, a localized conformational change takes place, involving 12 (Ile102-Ala113) out of the 44 residues of the loop. The pore is reduced to a sixth of its open state size. The conformational change can be achieved with a small perturbation and it is reversible once the perturbation is switched off (relaxation process). Other types of behaviour predominating at higher simulation temperatures are found for the loop, involving an extra conformational change in the Thr92-Asp96 loop segment. This conformational change completely closes the pore, but is not reversible under the simulation conditions. Both zones involved in the conformational changes contain or overlap the zones which were described previously, using other techniques, to be the most flexible zones of the loop.

Computer Graphics↗
PubMed1994

On the stability and plastic properties of the interior L3 loop in R. capsulatus porin. A molecular dynamics study.

Structural properties of Rhodobacter capsulatus porin are studied by molecular dynamics simulation using the GROMOS force field. Unconstrained simulations of the trimer and monomer show the trimer to be more stable than the isolated monomer. Simulations of the L3 loop inside the pore are used to assess its stability and plastic properties. Simulated annealing shows that the conformational space available to the L3 loop inside the pore is very large. Simulations at different temperatures show that the energy hypersurface around the open state is complex and flat. These studies also indicate four zones that are more flexible than the rest of the loop. Two of these are stabilized by the addition of the detergent molecule present in the X-ray structure. It is possible that the two remaining flexible zones, situated in the half of the loop facing the extracellular end of the porin molecule, residues Asp93-Gly98 and Arg110-Leu111, are involved in a mechanism for opening and closing of the pore.

Amino Acid Sequence↗
PubMed1993

Global characterization of protein secondary structures. Analysis of computer-modeled protein unfolding.

Analyses of structural and molecular shape changes undergone by a protein during an unfolding process are presented. The procedure, based on a spherical shape map method, provides a topological description of a three-dimensional macromolecular structure. Local properties of the backbone are used to derive a global characterization of its fold. A spherical shape map of backbone crossings is associated with a given macromolecular conformation. The map is built by classifying each point on the sphere according to the crossing pattern obtained when the backbone is observed along a direction defined by the center of the sphere and the chosen point. The surface of the sphere can be divided in equivalence classes. All the points within a given class correspond to directions from which the backbone has the same overcrossing pattern. Automatic computation and display of these equivalence classes is discussed, as is the implementation of the technique on a computer graphics workstation. The graphical manipulation simplifies the analysis of these maps when following a change in the conformation of the backbone. The procedure is illustrated with the results of a molecular dynamics computer simulation of the unfolding of the bacteriophage T4 glutaredoxin protein (in the form of its polyglycine model). The method gives a novel description of the differential structural stability for the characteristic secondary structural elements (alpha-helices and beta-sheets) present in the protein. Recognition of the persistence of structural elements over the simulation time is performed in an unbiased manner.

Algorithms↗
PubMed1993

[Brainstem auditory evoked potentials in low and high risk newborns].

Brainstem auditory evoked potentials (BAEP) were performed in a population of preterm infants of 32-34, 35-37 and 38-41 weeks of gestational age (GE) high risk newborns, and in 38-41 weeks GE low risk newborns. Statistical differences were found between both 38-41 weeks GE groups. High risk newborns showed longer latencies of waves III and V (P < 0.001), and I-III and I-V interwave intervals (P < 0.01). Our data show that auditory brainstem system suffer in high risk newborns. Results is discussed in relationship with other brainstem auditory evoked potentials studies in high risk newborns due it's clinical implications of present data.

Evoked Potentials, Auditory, Brain Stem↗
PubMed1992

A molecular model for the retinol binding protein-transthyretin complex.

A three-dimensional model for the complex between human serum retinol binding protein and transthyretin (formerly named prealbumin) is presented. The model was obtained by interactive rigid-body computer graphics docking and the characterization of the molecular surfaces in terms of fractal dimension. Available experimental data, as well as results from molecular dynamics calculations, support the proposed model.

Computer Graphics↗
PubMed1991

Stability and fluctuations of the potato carboxypeptidase A protein inhibitor fold: a molecular dynamics study.

A 120ps non-inertial solvent (NIS) molecular dynamics (MD) trajectory of the potato carboxypeptidase A protein inhibitor (PCI) was calculated and analyzed. It is shown that, in spite of a very low content of regular secondary structure, the PCI fold has a large degree of stability, judged from the fairly good agreement between the average MD and X-ray structures. The N-terminal and C-terminal regions behave differently, both in their isoatomic positional shifts with respect to the X-ray structure, and in atomic fluctuation pattern. Positional shifts up to 9A are detected in the exposed N-terminal region as it folds back on the inhibitor's core. This large deviation is most likely caused by the absence of the receptor protein or by the lack of supporting solvent molecules. In contrast, the C-terminal region, which is the primary contact site with the enzyme, has an average structure similar to the X-ray conformation; this feature is probably due to a hydrogen bond network to the central core of PCI. The C-terminal tail shows larger fluctuations than the core. The secondary contact site retains its structure in this simulation. The results evidence an intrinsically stable PCI fold which favors a spatially well defined, fairly flexible, structuration of the primary and secondary contact sites that optimizes PCI's interaction with its target enzyme.

Binding Sites↗