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PubMed1975

Supramolecular forms of actin from amoebae of Dictyostelium discoideum.

Actin purified from amoebae of Dictyostelium discoideum polymerizes into filaments at 24 degrees upon addition of KCl, as judged by a change in optical density at 232 nm and by electron microscopy. The rate and extent of formation of this supramolecular assembly and the optimal KCl concentrations (0.1 M) for assembly are similar to those of striated muscle actin. The apparent equilibrium constant for the monomer-polymer transition is 1.3 muM for both Dictyostelium and muscle actin. Although assembly of highly purified Dictyostelium actin monomers into individual actin filaments resembles that of muscle actin, Dictyostelium actin but not muscle actin was observed to assemble into two-dimensional nets in 10 mM CaCl2. The Dictyostelium actin also forms filament bundles which are 0.1 mum in diameter and which assemble in the presence of 5 mM MgCl2. These bundles formed from partially purified Dictyostelium actin preparations but not from highly purified preparations, suggesting that their formation may depend on the presence of another component. These actin bundles reconstituted in vitro resemble the actin-containing bundles found in situ by microscopy in many non-muscle cells.

Actins↗

PubMed2006

Ab initio study of hydrogen bonding and proton transfer in 3:1 FH:NH3 and FH:collidine complexes: structures and one- and two-bond coupling constants across hydrogen bonds.

Ab initio EOM-CCSD calculations have been performed on 3:1 FH:NH3 complexes at their own optimized MP2/6-31+G(d,p) geometries and at the optimized geometries in the hydrogen-bonding regions of corresponding 3:1 FH:collidine complexes. The isolated gas-phase equilibrium 3:1 FH:NH3 complex has an open structure with a proton-shared Fa-Ha-N hydrogen bond, while the isolated equilibrium 3:1 FH:collidine complex has a perpendicular structure with an Fa-Ha-N hydrogen bond that is on the ion-pair side of proton-shared. The Fa-N coupling constant ((2h)J(Fa-N)) for the equilibrium 3:1 FH:NH3 complex is large and negative, consistent with a proton-shared Fa-Ha-N hydrogen bond; (2h)JFb-Fa is positive, reflecting a short Fb-Fa distance and partial proton transfer from Fb to Fa across the Fb-Hb-Fa hydrogen bond. In contrast, (2h)JFa-N has a smaller absolute value and (2h)JFb-Fa is greater for the 3:1 FH:NH3 complex at the equilibrium 3:1 FH:collidine geometry, consistent with the structural characteristics of the Fa-Ha-N and Fb-Hb-Fa hydrogen bonds. Coupling constants computed at proton-transferred 3:1 FH:collidine perpendicular geometries are consistent with experimental coupling constants for the 3:1 FH:collidine complex in solution and indicate that the role of the solvent is to promote further proton transfer from Fa to N across the Fa-Ha-N hydrogen bond, and from Fb to Fa across the two equivalent Fb-Hb-Fa hydrogen bonds. The best correlations between experimental and computed coupling constants are found for complexes with perpendicular proton-transferred structures, one having the optimized geometry of a 3:1 FH:collidine complex at an Fa-Ha distance of 1.80 A, and the other at the optimized 3:1 FH:collidine geometry with distances derived from the experimental coupling constants. These calculations provide support for the proposed perpendicular structure of the 3:1 FH:collidine complex as the structure which exists in solution.

Hydrogen Bonding↗

PubMed1996

The metabolic productivity of the cell factory.

It is widely accepted that some performance function has been optimized during the evolution of metabolic pathways. One can study the nature of such a function by analogy with the industrial manufacturing world, in which there have been efforts over recent decades to optimize production chains, and in which it is now accepted that fluxes are not the only important system variables that determine process efficiency, because inventory turnover must also be considered. Inspired by the parallels between living cells and manufacturing factories, we propose that fluxes and transit time may have simultaneously been major targets of natural selection in the optimization of the design, structure and kinetic parameters of metabolic pathways. Accordingly we define the ratio of flux to transit time as a performance index of productivity in metabolic systems: it measures the efficiency with which stocks are administered, and facilitates comparison of a pathway in different steady states or in different tissues or organisms. For a linear chain of two enzymes, at a fixed total equilibrium constant, we have analysed the variation of flux, transit time and productivity index as functions of the equilibrium constants of the two steps. The results show that only the productivity index has a maximum, which represents a good compromise in optimizing flux and transit time. We have extended control analysis to the productivity index and derived the summation theorem that applies to it. For linear chains of different length with maximum productivity index values, the distribution of control coefficients with regard to the three parameters has a characteristic profile independent of the length of the chain. Finally, this control profile changes when other variables are optimized, and we compare the theoretical results with the control profile of the first steps of glycolysis in rat liver.

Animals↗

PubMed1988

Optimal hematologic variables for oxygen transport, including P50, hemoglobin cooperativity, hematocrit, acid-base status, and cardiac function.

The two important blood properties that affect O2 delivery are the O2 equilibrium curve (OEC) and blood viscosity with its subsequent effect on flow (cardiac output). To quantitate these properties blood OEC's were analyzed in terms of the Adair 4-step oxygenation model and the resulting parameters were used to construct a computer nomogram to reproduce the OEC at any combination of effectors that regulate P50 (pH, PCO2, and 2,3-DPG). In this way, the P50 could be changed systematically and the effects on overall O2 transport could be studied. Hematocrit-viscosity-cardiac output relationships were taken from the literature and validated using data from human subjects with various pathological states and high-altitude natives. A model was then developed, using the Bohr integration, to predict the O2 transport function of blood under a variety of conditions including exercise and hypoxia. The results indicate that the optimal hematocrit is about 43-45%, even in hypoxia. The optimal P50, however, depends on the availability of O2: a high P50 is not necessarily beneficial in hypoxia and high cardiac output states. This model and general approach should prove useful in the design of blood substitutes.

2,3-Diphosphoglycerate↗

PubMed2004

New insights into the pathophysiology of the dysnatremias: a quantitative analysis.

Recent theoretical considerations have played an important role in advancing our understanding of the physiological mechanisms responsible for perturbing the plasma water sodium concentration ([Na(+)](pw)) in health and disease. Central to these considerations is the original empirical relationship between the [Na(+)](pw) and total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) initially discovered by Edelman and colleagues (Edelman IS, Leibman J, O'Meara MP, and Birkenfeld LW. J Clin Invest 37: 1236-1256, 1958). The non-zero values of the slope and y-intercept in the Edelman equation are a consequence of the effects of the osmotic coefficient of Na(+) salts at physiological concentrations and Gibbs-Donnan and osmotic equilibrium. Moreover, in addition to Na(e), K(e), and TBW, the physiological components of the y-intercept in this equation play a role in modulating the [Na(+)](pw) and in the generation of the dysnatremias. In this review, the pathophysiological mechanisms underlying the generation and treatment of the dysnatremias are analyzed theoretically and quantitatively. Importantly, the non-zero values of both the slope and y-intercept in the Edelman equation result in several theoretical predictions that can be tested experimentally and have been mathematically incorporated into recently derived equations used to analyze both the generation and the optimal treatment of the dysnatremias. In addition, we review current concepts regarding 1) the role of Gibbs-Donnan and osmotic equilibrium in the determination of the [Na(+)](pw); 2) the modulating effect of osmotically inactive exchangeable Na(+) and K(+) on the [Na(+)](pw); 3) the effect of glucose on the [Na(+)](pw) as reflected by changes in Na(e), K(e), and TBW as well as changes in several components of the y-intercept resulting from the hyperglycemia; and 4) the complex role of K(+) in modulating the [Na(+)](pw).

Body Water↗

PubMed2004

Aquifex aeolicus dihydroorotase: association with aspartate transcarbamoylase switches on catalytic activity.

Dihydroorotase (DHOase) catalyzes the reversible condensation of carbamoyl aspartate to form dihydroorotate in de novo pyrimidine biosynthesis. The enzyme from Aquifex aeolicus, a hyperthermophilic organism of ancient lineage, was cloned and expressed in Escherichia coli. The purified protein was found to be a 45-kDa monomer containing a single zinc ion. Although there is no other DHOase gene in the A. aeolicus genome, the recombinant protein completely lacked catalytic activity at any temperature tested. However, DHOase formed an active complex with aspartate transcarbamoylase (ATCase) from the same organism. Whereas the k(cat) of 13.8 +/- 0.03 s(-1) was close to the value observed for the mammalian enzyme, the K (m)for dihydroorotate, 3.03 +/- 0.05 mM was 433-fold higher. Gel filtration and chemical cross-linking showed that the complex exists as a 240-kDa hexamer (DHO(3)-ATC(3)) and a 480-kDa duodecamer (DHO(6)-ATC(6)) probably in rapid equilibrium. Complex formation protects both DHOase and ATCase against thermal degradation at temperatures near 100 degrees C where the organism grows optimally. These results lead to the reclassification of both enzymes: ATCase, previously considered a Class C homotrimer, now falls into Class A, whereas the DHOase is a Class 1B enzyme. CD spectroscopy indicated that association with ATCase does not involve a significant perturbation of the DHOase secondary structure, but the visible absorption spectrum of a Co(2+)-substituted DHOase is appreciably altered upon complex formation suggesting a change in the electronic environment of the active site. The association of DHOase with ATCase probably serves as a molecular switch that ensures that free, uncomplexed DHOase in the cell remains inactive. At pH 7.4, the equilibrium ratio of carbamoyl aspartate to dihydroorotate is 17 and complex formation may drive the reaction in the biosynthetic direction.

Amino Acid Sequence↗

PubMed2004

Synthesis of alkylgalactosides using whole cells of Bacillus pseudofirmus species as catalysts.

Whole cells of alkaliphilic Bacillus pseudofirmus AR-199, induced for beta-galactosidase activity, were used for the synthesis of 1-hexyl-beta-d-galactoside and 1-octyl-beta-d-galactoside, respectively, by transglycosylation reaction between lactose and the corresponding alcohol acceptor. The product yield was strongly influenced by the initial water content in the reaction mixture. Water content of 10% (v/v) was optimal providing 3.6-36 mM hexyl galactoside from 10 to 150 mM lactose, and no secondary product hydrolysis. Product yield could be enhanced by supplementing the reaction mixture with more cells or partly replacing the product with fresh substrate, but was decreased with time to the initial equilibrium level. Cell permeabilisation or disruption resulted in increased reaction rate and higher product yield but was followed by product hydrolysis. Octyl galactoside synthesis using whole cells was optimal at water content of 2% (v/v) with a yield of 26%. The cells were immobilised in cryogels of polyvinyl alcohol for use in continuous process, where hexyl galactoside was produced with a constant yield of 50% from 50mM lactose for at least a week.

Alcohols↗

PubMed1998

Pharmacodynamic aspects of sustained release preparations.

The sustained release (SR) mode of drug administration has certain features that have an important impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). However, due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamic profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input rate which tends to minimize the body's counteraction to the drug's intervening effect on regulated physiological processes; and (c) it provides a continuous mode of drug administration. This important pharmacodynamic characteristic may produce, in certain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the same drug. For many drugs with non-concentration-dependent pharmacodynamics, the exposure time, rather than the AUC, is the relevant parameter and it can therefore be optimized by SR preparations. The slow input function may minimize hysteresis in cases where the site of action is not in a rapid equilibrium with the blood circulation. The pharmacodynamics of the desired effect(s) and/or adverse effect(s) may also be influenced by the site of administration, especially in cases where the drug is delivered directly to its site of action. These factors demonstrate the important influence of the mode of administration on the pharmacological and clinical outcomes. In addition, they highlight the need to include these pharmacodynamic considerations in all stages from drug development to the optimization of their clinical use.

Journal Article↗

PubMedDate not supplied

Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.

The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.

Animals↗

PubMed1998

Microquantification of cellular and in vitro F-actin by rhodamine phalloidin fluorescence enhancement.

Based on the enhancement of rhodamine phalloidin fluorescence after its binding to actin filaments we have developed a technique to quantify F-actin, drastically (>> 100 times) reducing consumption of the expensive fluorescent dye and sample material in comparison to previous methods. Depolymerization of F-actin is prevented by utilizing short incubation times and stabilization of the filaments by actin-binding proteins or formaldehyde. Equilibrium and kinetic mathematical models relating rhodamine fluorescence with F-actin concentrations were used to predict the optimal assay conditions. The method has been applied to measure relative and absolute F-actin concentrations in cytosolic fractions and stimulus-induced actin polymerization in neutrophils. The cells were lysed with octy1-beta-D-glucopyranoside, which is compatible with the assay due to its high critical micelle concentration. As the assay takes less than 1 h and eliminates all previously required washing or extraction steps, it is faster and much simpler than any other presented up to now for quantification of filamentous actin. Moreover, the method is unique for reliable and easy F-actin measurements in cell-free systems.

Actins↗

PubMed1991

Minimization of intermediate concentrations as a suggested optimality principle for biochemical networks. II. Time hierarchy, enzymatic rate laws, and erythrocyte metabolism.

The multiobjective problem of minimizing all intermediate concentrations is solved for a model of glycolysis, the pentose monophosphate shunt and the glutathione system in human erythrocytes. It turns out that one solution out of four obtained corresponds qualitatively to the real system. Furthermore, it is shown that for any reaction system, the mentioned optimality principle implies distinct time hierarchy in that some reactions are infinitely fast and subsist in quasi-equilibrium. Finally, the relationships to the standard method of deriving enzymatic rate laws are discussed.

Energy Metabolism↗

PubMed2004

An improved method for the enzymatic transformation of nucleosides into 5'-monophosphates.

An improved method to transform nucleosides into 5'-monophosphates using nucleoside phosphotransferase from Erwinia herbicola is reported. The method is based on the shift in the equilibrium state of the reaction to the formation of desired product due to its precipitation by Zn2+. Under optimal conditions, the extent of nucleoside transformations into nucleoside-5'-monophosphates were 41-91% (mol).

Enzyme Activation↗

PubMed2004

Osteryoung square wave stripping voltammetry at mercury film electrode for monitoring ultra trace levels of Tarabine PFS and its interaction with ssDNA.

The electrochemical oxidation and reduction behaviour of adsorbed species of antimetabolic antineoplastic agent Tarabine PFS (Cytosar-U) in Sorensen buffer solution of different pH values at an in situ-mercury film electrode (MFE) is studied using cyclic voltammetry (CV) and Osteryoung square-wave stripping voltammetry (OSWSV). Optimal experimental and operational parameters have been selected for the drug preconcentration and determination in aqueous medium. Based on the adsorption and accumulation of Tarabine PFS using Osteryoung square-wave anodic stripping voltammetry (OSWASV) at MFE, the drug is easily detected as 0.134 ng/ml (5.51 x 10(-10) M). Calibration plots have been constructed at different accumulation times. The standard deviation (n=10) at a concentration level of 6 x 10(-8) M Tarabine PFS is 0.062. The interaction of ssDNA with the drug under the optimal conditions at pH 7.7 has been studied. The formal potentials E degrees and E degrees ' and the equilibrium constants K(1) and K(2) have been calculated for the free form of Tarabine PFS and the bonded form with ssDNA, respectively. It was found that K(2) value for the bonded oxidized form is 298 times than that of K(1) for the bonded reduced form. Therefore, ssDNA has been found to interact strongly with the oxidized form of the drug. The method has been used for the nanogram determination of ssDNA with 1.9% variation coefficient. Detection limit of 3 ng/ml ssDNA has been achieved. Possible interfering organic compounds, cations and anions have been tested. The method has been applied for the drug determination in urine samples, down to 0.23 ng/ml could be easily achieved in such samples.

Animals↗

PubMed1999

Binding affinities of gallotannin analogs with bovine serum albumin: ramifications for polyphenol-protein molecular recognition.

A series of gallotannin analogs were prepared by chemical synthesis, and their affinity for the test-case protein bovine serum albumin was measured by equilibrium dialysis. The structure/activity data obtained suggest that the naturally occurring gallotannins, in fact, do not represent the optimal protein recognition agents amongst polyphenolated templates.

Flavonoids↗

PubMed1980

Quantitative gas chromatographic determination of two oxidized metabolites of the diuretic mefruside in human urine, plasma and red blood cells.

A gas chromatographic method is reported for the quantitative analysis of two metabolites of mefruside, viz., 5-oxo-mefruside (mefruside lactone) and its hydroxy-carboxylic acid analogue in human body fluids. Use was made of extractive methylation as the derivatization technique, and quantitation was achieved, with a suitable internal standard, by means of a nitrogen-sensitive detector. Because the two metabolites are linked chemically through a lactone-open acid equilibrium, interconversion prior to their separation had to be avoided. A pH partitioning study was performed to find optimal separation conditions. The lactone could be extracted quantitatively at pH 7.4, without any trace of co-extracted hydroxy acid. The latter was extracted either at pH 2 directly (in the case of plasma and urine), or after conversion to the lactone at pH 7.4 (in the case of red cells or whole blood). Concentrations down to 25 ng per sample of both compounds could be analysed with a standard deviation of 5%. The two metabolites of mefruside equilibrated instantaneously between red cells and plasma in vitro. At 37 degrees, the red cell/plasma concentration ratio was 20 for the lactone, but only 0.1 for the open acid compound. 5-Oxo-mefruside was able to displace mefruside from its red blood cell binding sites in vitro.

Carboxylic Acids↗

PubMed1993

Characterization of the binding and comparison of the distribution of benzodiazepine receptors labeled with [3H]diazepam and [3H]alprazolam.

The binding characteristics of [3H]diazepam and [3H]alprazolam were obtained by in vitro analysis of sections of rat brain. Dissociation, association, and saturation analyses were performed to optimize the conditions for obtaining selective labeling of benzodiazepine receptors with the two tritiated compounds. Both drugs approached equilibrium rapidly in vitro. Rosenthal analysis (Scatchard plot) of the saturation data indicated a similar finite number of receptors was being occupied by both ligands. Competition studies, using various ligands to inhibit both [3H]diazepam and [3H]alprazolam indicated that these two compounds bind to the tissue sections as typical benzodiazepine drugs and apparently do not overlap onto other subtypes of receptors. These experiments were performed by both binding assay in tissue sections and by light microscopic autoradiography. The major difference between the labeling of the two compounds is represented by the peripheral benzodiazepine sites, which are recognized by [3H]diazepam, but not occupied by [3H]alprazolam (at nanomolar concentrations). This difference was readily apparent in the autoradiograms. Other pharmacokinetic or pharmacodynamic properties must distinguish these two benzodiazepines.

Alprazolam↗

PubMed2004

Polarization consistent basis sets. V. The elements Si-Cl.

Polarization consistent basis sets, optimized for density functional calculations, are proposed for the elements Si-Cl. Their performance for atomization energies, equilibrium geometries, harmonic vibrational frequencies, and associated infrared intensities is compared with other commonly used basis sets. Atomization energies can be predicted to within 0.01 kJ/mol per atom of the basis set limit by extrapolation of the pc-2, -3, and -4 results. Equilibrium bond distances and harmonic vibrational frequencies can be calculated to within 10(-5) A and 0.5 cm(-1), respectively, of the basis set limit. The pc-n basis sets are shown to give comparable or better accuracy than other alternatives, while containing fewer or equal number of primitive basis functions.

Journal Article↗

PubMed2005

Density guided importance sampling: application to a reduced model of protein folding.

MOTIVATION: Monte Carlo methods are the most effective means of exploring the energy landscapes of protein folding. The rugged topography of folding energy landscapes causes sampling inefficiencies however, particularly at low, physiological temperatures. RESULTS: A hybrid Monte Carlo method, termed density guided importance sampling (DGIS), is presented that overcomes these sampling inefficiencies. The method is shown to be highly accurate and efficient in determining Boltzmann weighted structural metrics of a discrete off-lattice protein model. In comparison to the Metropolis Monte Carlo method, and the hybrid Monte Carlo methods, jump-walking, smart-walking and replica-exchange, the DGIS method is shown to be more efficient, requiring no parameter optimization. The method guides the simulation towards under-sampled regions of the energy spectrum and recognizes when equilibrium has been reached, avoiding arbitrary and excessively long simulation times. AVAILABILITY: Fortran code available from authors upon request. CONTACT: m.j.parker@leeds.ac.uk.

Algorithms↗