Petri Net Based Metabolic Network Parameters Fitting with GPU Acceleration

Classical Petri net has been applied into biological analysis, especially as a qualitative model for biochemical pathways analysis, but lack of the ability for quantitative kinetic simulations. In our study, we presented an integration work of the qualitative model–Petri nets with the quantitative approach‐ordinary differential equations (ODEs) for the modeling and analysis of metabolic networks. As an application of our study, the computational modeling of arachidonic acid (AA) biochemical network was provided. A Petri net was set up to present the constraint‐based dynamic simulations on AA metabolic network combined with the validated ODEs model. Furthermore, Graphics Processing Unit (GPU) was adopted to accelerate the calculation of kinetic parameters unavailable from experiments. Our results have indicated that the proposed simulation method was practicable and useful with GPU acceleration, and provides new clues for the large‐scale qualitative and quantitative models of biochemical networks.     

Automatic identification of model reductions for discrete stochastic simulation

Multiple time scales in cellular chemical reaction systems present a challenge for the efficiency of stochastic simulation. Numerous model reductions have been proposed to accelerate the simulation of chemically reacting systems by exploiting time scale separation. However, these are often identified and deployed manually, requiring expert knowledge. This is time-consuming, prone to error, and opportunities for model reduction may be missed, particularly for large models. We propose an automatic model analysis algorithm using an adaptively weighted Petri net to dynamically identify opportunities for model reductions for both the stochastic simulation algorithm and tau-leaping simulation, with no requirement of expert knowledge input. Results are presented to demonstrate the utility and effectiveness of this approach.     

Time-resolved CIDNP in laser flash photolysis of di-tert-butyl ketone. Multiplet versus net effects

Based on the principles of Fourier spectroscopy of non-equilibrium systems a method for the separate determination of net and multiplet type CIDNP effects in chemical reactions is developed. Further, a theoretical model for the analysis of time evolution of high-field CIDNP following pulse initiated reactions is extended to cover multiplet effects. Experimental data on multiplet and net CIDNP effects created by laser photolysis of di-tert-butyl ketone are presented and verify the theoretical conclusions. The observed magnitudes of net and multiplet effects support the Pedersen-Freed high-field radical pair theory.     

Chord intercepts in the two-dimensional cell model

The two-dimensional cell model is defined by the following conditions of its formation: athermal nuclei may be randomly (Poisson) distributed in a thin amorphous film. From these nuclei spherulites may start to grow instantaneously, circularly, and at the same rate. Where two spherulites touch growth stops, and all points of contact form a straight intersection between neighboring spherulites. Finally, if the film contains spherulites only, each spherulite (cell) is completely limited by straight intersections, forming an irregular polygon. All irregular polygons of the film together form a planar irregular net of straight intersections. In quantitative microscopy this net is characterized by a “lineal analysis.” A straight line (Rosiwal's line) is arbitrarily put into the plane of the net. The net divides Rosiwal's line into chord intercepts of different lengths. The distribution of these lengths is analytically derived in the present paper by use of the theory of probability.     

Active site structure of class I ribonucleotide reductase intermediate X: a density functional theory analysis of structure, energetics, and spectroscopy

Several models for the active site structure of class I ribonucleotide reductase (RNR) intermediate X have been studied in the work described in this paper, using broken-symmetry density functional theory (DFT) incorporated with the conductor-like screening (COSMO) solvation model. The calculated properties, including geometries, spin states, 57Fe, 1H, and 17O hyperfine tensors, M?ssbauer isomer shifts, and quadrupole splittings, and the estimation of the Fe(IV) d-d transition energies have been compared with the available experimental values. On the basis of the detailed analysis and comparisons, we propose a definite form for the active site structure of class I RNR intermediate X, which contains an Fe1(III)Fe2(IV) center (where Fe1 is the iron site closer to Tyr122, and the two iron sites are high-spin antiferromagnetically coupled to give a total 1/2 net spin), two mu-oxo bridges, one terminal water which binds to Fe1(III) and also H-bonds to both side chains of Asp84 and Glu238, and one bidentate carboxylate group from the side chain of Glu115.     

Stable isotope labelling and FPLC-ICP-SFMS for the accurate determination of clinical iron status parameters in human serum

Iron is involved in the function of all living cells and, in fact, many diseases arise from imbalances in iron homeostasis. Therefore, the development of analytical methodologies to improve and automate the measurement of clinical indices of iron status has increased tremendously over the years. This work describes the development of two complementary methodologies to evaluate transferrin (Tf) saturation, total iron-binding capacity (TIBC), unsaturated iron-binding capacity (UIBC) and serum iron based on the use of iron-selective monitoring by inductively coupled plasma mass spectrometry (ICP-MS). The first methodology is based on the saturation of transferrin (Tf) with natural Fe3+ followed by separation of the different sialoforms in an anion exchange column (Mono-Q) to quantify the iron in each Tf sialoform and total Tf by ICP-MS using post-column isotope dilution analysis. In the second part, the saturation is done with an iron tracer (57Fe) and the application of pattern deconvolution analysis permits the direct quantification of the Tf saturation, the serum iron and the unsaturated iron-binding capacity. These strategies are validated by using a reference serum certified for total Tf and tested also in serum samples from individuals suffering from hemochromatosis and Fe-supplemented patients. The results obtained for all the parameters related to Fe status were in good agreement with those obtained by clinical tests. The use of stable isotope labelling in connection with the on-line coupling of fast protein liquid chromatography (FPLC) to ICP-MS allows the accurate determination of several parameters of great clinical relevance in iron homeostasis by means of two independent chromatographic runs. The main advantage of the proposed methodology is the number of parameters that can be simultaneously obtained.     

Structure and Mechanism Leading to Formation of the Cysteine Sulfinate Product Complex of a Biomimetic Cysteine Dioxygenase Model

Cysteine dioxygenase is a unique nonheme iron enzyme that is involved in the metabolism of cysteine in the body. It contains an iron active site with an unusual 3‐His ligation to the protein, which contrasts with the structural features of common nonheme iron dioxygenases. Recently, some of us reported a truly biomimetic model for this enzyme, namely a trispyrazolylborato iron(II) cysteinato complex, which not only has a structure very similar to the enzyme–substrate complex but also represents a functional model: Treatment of the model with dioxygen leads to cysteine dioxygenation, as shown by isolating the cysteine part of the product in the course of the work‐up. However, little is known on the conversion mechanism and, so far, not even the structure of the actual product complex had been characterised, which is also unknown in case of the enzyme. In a multidisciplinary approach including density functional theory calculations and X‐ray absorption spectroscopy, we have now determined the structure of the actual sulfinato complex for the first time. The Cys‐SO₂^? functional group was found to be bound in an η²‐O,O‐coordination mode, which, based on the excellent resemblance between model and enzyme, also provides the first support for a corresponding binding mode within the enzymatic product complex. Indeed, this is again confirmed by theory, which had predicted a η²‐O,O‐binding mode for synthetic as well as the natural enzyme.     

Volumetric emission of argon plasmas in the presence of vapors of Fe,Si, and Al

The net volumetric emission was calculated for argon plasmas at atmospheric pressure in the presence of metal vapors for different elements, over the temperature range from 3000 to 30,000 K. The computations are based on the escape factor model, using a semi-empirical method for the determination of line profiles and line broadening effects. Results for iron, .silicon, and aluminum show an important influence of the presence of even the smallest concentrations of the metal vapors on the net emission coefficient of the plasma. The effect is strongest for iron, followed by aluminum and .silicon. Special attention is given to self-absorption effects which are most important in the first millimeter o% the optical path of the emitted radiation. The effect is incorporated into the calculation procedure of the net emission coefficient and can be used as a volumetric energy sink as long as the absorption length is shorter than the radius of the control volume used in the computation scheme.     

Differences and Comparisons of the Properties and Reactivities of Iron(III)–hydroperoxo Complexes with Saturated Coordination Sphere

Heme and nonheme monoxygenases and dioxygenases catalyze important oxygen atom transfer reactions to substrates in the body. It is now well established that the cytochrome P450 enzymes react through the formation of a high‐valent iron(IV)–oxo heme cation radical. Its precursor in the catalytic cycle, the iron(III)–hydroperoxo complex, was tested for catalytic activity and found to be a sluggish oxidant of hydroxylation, epoxidation and sulfoxidation reactions. In a recent twist of events, evidence has emerged of several nonheme iron(III)–hydroperoxo complexes that appear to react with substrates via oxygen atom transfer processes. Although it was not clear from these studies whether the iron(III)–hydroperoxo reacted directly with substrates or that an initial O?O bond cleavage preceded the reaction. Clearly, the catalytic activity of heme and nonheme iron(III)–hydroperoxo complexes is substantially different, but the origins of this are still poorly understood and warrant a detailed analysis. In this work, an extensive computational analysis of aromatic hydroxylation by biomimetic nonheme and heme iron systems is presented, starting from an iron(III)–hydroperoxo complex with pentadentate ligand system (L₅²). Direct C?O bond formation by an iron(III)–hydroperoxo complex is investigated, as well as the initial heterolytic and homolytic bond cleavage of the hydroperoxo group. The calculations show that [(L₅²)Fe^III(OOH)]²⁺ should be able to initiate an aromatic hydroxylation process, although a low‐energy homolytic cleavage pathway is only slightly higher in energy. A detailed valence bond and thermochemical analysis rationalizes the differences in chemical reactivity of heme and nonheme iron(III)–hydroperoxo and show that the main reason for this particular nonheme complex to be reactive comes from the fact that they homolytically split the O?O bond, whereas a heterolytic O?O bond breaking in heme iron(III)–hydroperoxo is found.     

Development of Petri Net-Based Dynamic Model for Improved Production of Farnesyl Pyrophosphate by Integrating Mevalonate and Methylerythritol Phosphate Pathways in Yeast

In this case study, we designed a farnesyl pyrophosphate (FPP) biosynthetic network using hybrid functional Petri net with extension (HFPNe) which is derived from traditional Petri net theory and allows easy modeling with graphical approach of various types of entities in the networks together. Our main objective is to improve the production of FPP in yeast, which is further converted to amorphadiene (AD), a precursor of artemisinin (antimalarial drug). Natively, mevalonate (MEV) pathway is present in yeast. Methyl erythritol phosphate pathways (MEP) are present only in higher plant plastids and eubacteria, but not present in yeast. IPP and DAMP are common isomeric intermediate in these two pathways, which immediately yields FPP. By integrating these two pathways in yeast, we augmented the FPP synthesis approximately two folds higher (431.16 U/pt) than in MEV pathway alone (259.91 U/pt) by using HFPNe technique. Further enhanced FPP levels converted to AD by amorphadiene synthase gene yielding 436.5 U/pt of AD which approximately two folds higher compared to the AD (258.5 U/pt) synthesized by MEV pathway exclusively. Simulation and validation processes performed using these models are reliable with identified biological information and data.     

Polyethylene fiber formation in tubular flow. II. Discussion of precursor formation and nucleation time analysis

This is a continuation of the preceeding paper, Part I, and presents a discussion of the nature of the precursor structure formation process observed in the flow-induced crystallization experiments described in I. A discussion of stress-induced crystallization theory as applied to these experiments is also given and a first-order analysis of crystal nucleation rates is presented. Conclusions regarding the nature of flow-induced crystallization and our current ability to quantitatively model the overall process are also presented.     

First-principle molecular dynamics with ultrasoft pseudopotentials: parallel implementation and application to extended bioinorganic systems

We present a plane-wave ultrasoft pseudopotential implementation of first-principle molecular dynamics, which is well suited to model large molecular systems containing transition metal centers. We describe an efficient strategy for parallelization that includes special features to deal with the augmented charge in the contest of Vanderbilt's ultrasoft pseudopotentials. We also discuss a simple approach to model molecular systems with a net charge and/or large dipole/quadrupole moments. We present test applications to manganese and iron porphyrins representative of a large class of biologically relevant metalorganic systems. Our results show that accurate density-functional theory calculations on systems with several hundred atoms are feasible with access to moderate computational resources.     

Magnetoresistance effect,Runge–Lenz vector,and the torque vector due to anisotropy of electron orbits in cubic lattices submitted to the action of a constant magnetic field

Parameters due to an anisotropic character of the electron orbits in cubic metals submitted to the action of an external magnetic field are calculated. These parameters are, in the first step, a nonzero value of the metal magnetoresistance and—in the second step—the nonvanishing electron torque vector and the Runge–Lenz vector. Both these vectors depend on the electron angular momentum in the crystal lattices, which is also examined together with the radius of curvature of the electron orbits. The calculation of magnetoresistance is specified to the case of the body‐centered cubic lattice of metallic iron for which a comparison of the theory with the experimental data for magnetoresistance is also presented. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Study of the Drying Behavior of Poly(vinyl alcohol) Aqueous Solution

This paper deals with the drying behavior of poly(vinyl alcohol) aqueous solution containing an active substance and placed into a Petri box. The objective is to reduce the drying time while respecting some constraints. To succeed, it is important to understand complex mechanisms governing heat and mass transfers. During the drying, the product thickness shrinks and its properties evolve. Drying kinetics in convective and infrared radiation are presented.     

A theoretical study on the electronic structures and equilibrium constants evaluation of Deferasirox iron complexes

Elemental iron is essential for cellular growth and homeostasis but it is potentially toxic to the cells and tissues. Excess iron can contribute in tumor initiation and tumor growth. Obviously, in iron overload issues using an iron chelator in order to reduce iron concentration seems to be vital. This study presents the density functional theory calculations of the electronic structure and equilibrium constant for iron-deferasirox (Fe-DFX) complexes in the gas phase, water and DMSO. A comprehensive study was performed to investigate the Deferasirox-iron complexes in chelation therapy. Calculation was performed in CAMB3LYP/6-31G(d,p) to get the optimized structures for iron complexes in high and low spin states. Natural bond orbital and quantum theory of atoms in molecules analyses was carried out with B3LYP/6-311G(d,p) to understand the nature of complex bond character and electronic transition in complexes. Electrostatic potential effects on the complexes were evaluated using the CHelpG calculations. The results indicated that higher affinity for Fe(III) is not strictly a function of bond length but also the degree of Fe–X (X = O,N) covalent bonding. Based on the quantum reactivity parameters which have been investigated here, it is possible reasonable design of the new chelators to improve the chelator abilities.     

The Structure of the BfrB-Bfd Complex Reveals Protein-Protein Interactions Enabling Iron Release from Bacterioferritin

Ferritin-like molecules are unique to cellular iron homeostasis because they can store iron at concentrations much higher than those dictated by the solubility of Fe(3+). Very little is known about the protein interactions that deliver iron for storage or promote the mobilization of stored iron from ferritin-like molecules. Here, we report the X-ray crystal structure of Pseudomonas aeruginosa bacterioferritin (Pa-BfrB) in complex with bacterioferritin-associated ferredoxin (Pa-Bfd) at 2.0 ? resolution. As the first example of a ferritin-like molecule in complex with a cognate partner, the structure provides unprecedented insight into the complementary interface that enables the [2Fe-2S] cluster of Pa-Bfd to promote heme-mediated electron transfer through the BfrB protein dielectric (～18 ?), a process that is necessary to reduce the core ferric mineral and facilitate mobilization of Fe(2+). The Pa-BfrB-Bfd complex also revealed the first structure of a Bfd, thus providing a first view to what appears to be a versatile metal binding domain ubiquitous to the large Fer2_BFD family of proteins and enzymes with diverse functions. Residues at the Pa-BfrB-Bfd interface are highly conserved in Bfr and Bfd sequences from a number of pathogenic bacteria, suggesting that the specific recognition between Pa-BfrB and Pa-Bfd is of widespread significance to the understanding of bacterial iron homeostasis.     

Brain iron metabolism and its perturbation in neurological diseases

Abstract  

Enormous advances have been made in the last decade in understanding iron metabolism and iron homeostasis at both the cellular and the systemic level. This includes the identification of genes and proteins involved in iron transport, such as the ferric reductase DcytB, the proton-coupled ferrous (divalent) iron transporter DMT1, the iron exporter ferroportin and the membrane-bound ferroxidase hephaestin. The modulation of their translation by the iron regulatory protein (IRP) system has also been identified together with the impressive signalling cascades involved in regulating the chef d’orchestre of systemic iron homeostasis, hepcidin. However, exactly how the brain regulates fluxes and storage of iron between neurons, oligodendrocytes, astrocytes and microglial cells remains an enigma. In this review we discuss the possible mechanisms which may be involved in the transfer of iron across the blood–brain barrier, together with the possible role played by astrocytes. The consequences of iron deficiency and iron excess on brain function are described. Finally, various neurodegenerative diseases, where accumulation of iron may be important in the pathogenesis, are presented as well as the possible use of iron chelators to diminish disease progression.     

Effects of compositional defects on small polaron hopping in micas

Hartree-Fock calculations and electron transfer (ET) theory were used to model the effects of compositional defects on ET in the brucite-like octahedral sheet of mica. ET was modeled as an Fe(IIIII) valence interchange reaction across shared octahedral edges of the M2-M2 iron sublattice. The model entails the hopping of localized electrons and small polaron behavior. Hartree-Fock calculations indicate that substitution of F for structural OH bridges increases the reorganization energy lambda, decreases the electronic coupling matrix element V(AB), and thereby substantially decreases the hopping rate. The lambda increase arises from modification of the metal-ligand bond force constants, and the V(AB) decrease arises from reduction of superexchange interaction through anion bridges. Deprotonation of an OH bridge, consistent with a possible mechanism of maintaining charge neutrality during net oxidation, yields a net increase in the ET rate. Although substitution of Al or Mg for Fe in M1 sites distorts the structure of adjacent Fe-occupied M2 sites, the distortion has little net impact on ET rates through these M2 sites. Hence the main effect of Al or Mg substitution for Fe, should it occur in the M2 sublattice, is to block ET pathways. Collectively, these findings pave the way for larger-scale oxidation/reduction models to be constructed for realistic, compositionally diverse micas.     

Changes in amniotic fluid and umbilical cord serum proteomic profiles of foetuses with intrauterine growth retardation

Foetal growth is a result of a complex net of processes, requiring coordination within the maternal, placental, and foetal compartments, the imbalance or lack of which may lead to intrauterine growth restriction (IUGR). IUGR is the major cause of perinatal morbidity and mortality, and is also related to enhanced morbidity and metabolic abnormalities later in life. In the present study, the protein profiles of umbilical cord serum (UCS) and amniotic fluid (AF) of ten IUGR and ten appropriate for gestational age newborns have been analysed by 2-DE, and nanoHPLC-Chip/MS technology. A total of 18 and 13 spots were found to be differentially expressed (p<0.01) in UCS and AF respectively. The unique differentially expressed proteins identified by MS/MS analysis were 14 in UCS, and 11 in AF samples. Protein gene ontology classification indicate that 21% of proteins are involved in inflammatory response, 20% in immune response, while a smaller proportion are related to transport, blood pressure, and coagulation. These results support the conclusion that the IUGR condition alters the expression of proteins involved in the coagulation process, immune mechanisms, blood pressure and iron and copper homeostasis control, offering a new insight into IUGR pathogenesis.