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PubMed2002

Cubic mesophase in an unsymmetrical alkyl ammonium salt. Synthesis and structural model.

N,N,N-butylethylpentylpropylammonium iodide 4 and related molecules have been selectively synthesised from commercially available aldehydes, amines and alkyl iodides using a reductive alkylation procedure. The crystalline texture of 4 obtained on cooling is optically isotropic between crossed polarisers, indicating a cubic structure. Differential scanning calorimetry (DSC, +10 K min-1) reveals a glass phase transition at -59 degrees C and a melting point at 192 degrees C. The melting entropy (23.9 J mol-1 K-1) indicates a first-order transition between a highly disordered mesophase and the isotropic liquid. Powder X-ray diffraction patterns were indexed in the cubic system (a = 14.08A; Pm3n space group). In this cell, the molecular packing with Z = 6 corresponds to a rather low compactness of 65%. Iodine and tetraalkylammonium ions occupy positions with a 4m2 site symmetry. These highly symmetrical states may be generated by stepwise rotation of the ammonium cation. The same structural model for orientationally disordered crystal (ODIC) phases can be applied to a series of tetraalkylammonium bromides and iodides.

Journal Article↗

PubMed2005

Structural models and atomic distribution of bimetallic nanoparticles as investigated by X-ray absorption spectroscopy.

In this report, we describe a general methodology to determine the extent of alloying or atomic distribution quantitatively in bimetallic nanoparticles (NPs) by X-ray absorption spectroscopy (XAS). The structural parameters determined in these studies serve as a quantitative index and provide a general route to determine the structural aspects of the bimetallic NPs. We have derived various types of possible structural models based on the extent of alloying and coordination number parameters of bimetallic NPs. We also discussed the nature of homo- and heterometallic interactions in bimetallic NPs based on the extent of alloying. Herein, we use carbon-supported platinum-ruthenium bimetallic nanoparticles to demonstrate the proposed methodology, and this can be extended further to get more insights into the alloying extent or atomic distribution of other bimetallic systems. The results demonstrated in this paper open up methods to determine the atomic distribution of bimetallic NPs, which is an extremely important parameter that strongly influences the physicochemical properties of NPs and their applications.

Journal Article↗

PubMed2006

Parameter optimization and field validation of the functional-structural model GREENLAB for maize.

BACKGROUND AND AIMS: There are three reasons for the increasing demand for crop models that build the plant on the basis of architectural principles and organogenetic processes: (1) realistic concepts for developing new crops need to be guided by such models; (2) there is an increasing interest in crop phenotypic plasticity, based on variable architecture and morphology; and (3) engineering of mechanized cropping systems requires information on crop architecture. The functional-structural model GREENLAB was recently presented that simulates resource-dependent plasticity of plant architecture. This study introduces a new methodology for crop parameter optimization against measured data called multi-fitting, validates the calibrated model for maize with independent field data, and describes a technique for 3D visualization of outputs. METHODS: Maize was grown near Beijing during the 2000, 2001 and 2003 (two sowing dates) summer seasons in a block design with four to five replications. Detailed morphological and topological observations were made on the plant architecture throughout the development of the four crops. Data obtained in 2000 was used to establish target files for parameter optimization using the generalized least square method, and parameter accuracy was evaluated by coefficient of variance. In situ plant digitization was used to establish 3D symbol files for organs that were then used to translate model outputs directly into 3D representations for each time step of model execution. KEY RESULTS AND CONCLUSIONS: Multi-fitting against several target files obtained at different growth stages gave better parameter accuracy than single fitting at maturity only, and permitted extracting generic organ expansion kinetics from the static observations. The 2000 model gave excellent predictions of plant architecture and vegetative growth for the other three seasons having different temperature regimes, but predictions of inter-seasonal variability of biomass partitioning during grain filling were less accurate. This was probably due to insufficient consideration of processes governing cob sink size and terminal leaf senescence. Further perspectives for model improvement are discussed.

Agriculture↗

PubMed1998

The initiation and the maintenance of dieting: structural models for large-scale longitudinal investigations.

OBJECTIVE: Female adolescents who engage in weight loss dieting often experience negative physical and psychological consequences. To reduce the occurrence of dieting, we need information about the factors associated with its initiation and maintenance. This paper outlines two separate structural models developed specifically for that purpose. METHOD: The theoretical rationale that informed the development of each of the models was derived from careful reviews of the literature on disordered eating, and from relevant psychological theoretical and empirical literature. RESULTS: Separate theoretical models are identified for the initiation of dieting, in which the core component is social influence, and for the maintenance of dieting, which assumes that differences in the persistence of dieting are best understood as motivational. Each model also incorporates individual differences and variables that are hypothesized to mediate the specific effects on dieting or to operate as moderators of the relationship. DISCUSSION: The operationalization of the components of the models and their application within large-scale longitudinal studies are discussed in relation to the need for systematic investigations of the way dieting begins and how it escalates or is maintained.

Adolescent↗

PubMed2003

Kinetic characterization, structure modelling studies and crystallization of Trypanosoma brucei enolase.

In this article, we report the results of an analysis of the glycolytic enzyme enolase (2-phospho-d-glycerate hydrolase) of Trypanosoma brucei. Enolase activity was detected in both bloodstream-form and procyclic insect-stage trypanosomes, although a 4.5-fold lower specific activity was found in the cultured procyclic homogenate. Subcellular localization analysis showed that the enzyme is only present in the cytosol. The T. brucei enolase was expressed in Escherichia coli and purified to homogeneity. The kinetic properties of the bacterially expressed enzyme showed strong similarity to those values found for the natural T. brucei enolase present in a cytosolic cell fraction, indicating a proper folding of the enzyme in E. coli. The kinetic properties of T. brucei enolase were also studied in comparison with enolase from rabbit muscle and Saccharomyces cerevisiae. Functionally, similarities were found to exist between the three enzymes: the Michaelis constant (Km) and KA values for the substrates and Mg2+ are very similar. Differences in pH optima for activity, inhibition by excess Mg2+ and susceptibilities to monovalent ions showed that the T. brucei enolase behaves more like the yeast enzyme. Alignment of the amino acid sequences of T. brucei enolase and other eukaryotic and prokaryotic enolases showed that most residues involved in the binding of its ligands are well conserved. Structure modelling of the T. brucei enzyme using the available S. cerevisiae structures as templates indicated that there are some atypical residues (one Lys and two Cys) close to the T. brucei active site. As these residues are absent from the human host enolase and are therefore potentially interesting for drug design, we initiated attempts to determine the three-dimensional structure. T. brucei enolase crystals diffracting at 2.3 A resolution were obtained and will permit us to pursue the determination of structure.

Amino Acid Sequence↗

PubMed2002

A 3-D structural model of solid self-assembled chlorophyll a/H(2)O from multispin labeling and MAS NMR 2-D dipolar correlation spectroscopy in high magnetic field.

Magic angle spinning (MAS) NMR with Lee-Goldburg cross-polarization (LG-CP) is used to promote long-range heteronuclear transfer of magnetization and to constrain a structural model for uniformly labeled chlorophyll a/H(2)O. An effective maximum transfer range d(max) can be determined experimentally from the detection of a gradually decreasing series of intramolecular correlations with the (13)C along the molecular skeleton. To probe intermolecular contacts, d(max) can be set to approximately 4.2 A by choosing an LG-CP contact time of 2 ms. Long-range (1)H-(13)C correlations are used in conjunction with carbon and proton aggregation shifts to establish the stacking of the chlorophyll a (Chl a) molecules. First, high-field (14.1 T) 2-D MAS NMR homonuclear ((13)C-(13)C) dipolar correlation spectra provide a complete assignment of the carbon chemical shifts. Second, proton chemical shifts are obtained from (1)H-(13)C heteronuclear dipolar correlation spectroscopy in high magnetic field. The shift constraints and long-range (1)H-(13)C intermolecular correlations reveal a 2-D stacking homologous to the molecular arrangement in crystalline solid ethyl-chlorophyllide a. A doubling of a small subset of the carbon resonances, in the 7-methyl region of the molecule, provides evidence for two marginally different well-defined molecular environments. Evidence is found for the presence of neutral structural water molecules forming a hydrogen-bonded network to stabilize Chl a sheets. In line with the microcrystalline order observed for the rings, the long T(1)'s, and absence of conformational shifts for the (13)C in the phytyl tails, it is proposed that the Chl a form a rigid 3-D space-filling structure. Probably the only way this can be realized with the sheets is by forming bilayers with interpenetration of elongated tails. Such a 3-D space-filling organization of the aggregated Chl a from MAS NMR would match existing models inferred from electron microscopy and low-resolution X-ray powder diffraction, while a micellar model based on neutron diffraction and antiparallel stacking observed in solution can be discarded.

Carbon Isotopes↗

PubMed2004

Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal.

CPT I (carnitine palmitoyltransferase I) catalyses the conversion of palmitoyl-CoA into palmitoylcarnitine in the presence of L-carnitine, facilitating the entry of fatty acids into mitochondria. We propose a 3-D (three-dimensional) structural model for L-CPT I (liver CPT I), based on the similarity of this enzyme to the recently crystallized mouse carnitine acetyltransferase. The model includes 607 of the 773 amino acids of L-CPT I, and the positions of carnitine, CoA and the palmitoyl group were assigned by superposition and docking analysis. Functional analysis of this 3-D model included the mutagenesis of several amino acids in order to identify putative catalytic residues. Mutants D477A, D567A and E590D showed reduced L-CPT I activity. In addition, individual mutation of amino acids forming the conserved Ser685-Thr686-Ser687 motif abolished enzyme activity in mutants T686A and S687A and altered K(m) and the catalytic efficiency for carnitine in mutant S685A. We conclude that the catalytic residues are His473 and Asp477, while Ser687 probably stabilizes the transition state. Several conserved lysines, i.e. Lys455, Lys505, Lys560 and Lys561, were also mutated. Only mutants K455A and K560A showed decreases in activity of 50%. The model rationalizes the finding of nine natural mutations in patients with hereditary L-CPT I deficiencies.

Amino Acid Sequence↗

PubMed2002

Origin of the stability of Ge(105) on si: a new structure model and surface strain relaxation.

The structure of Ge(105)-(1 x 2) grown on Si(105) is examined by scanning tunneling microscopy (STM) and first-principles calculations. The morphology evolution with an increasing amount of Ge deposited documents the existence of a tensile surface strain in Si(105) and its relaxation with increasing coverage of Ge. A detailed analysis of high-resolution STM images and first-principles calculations produce a new stable model for the Ge(105)-(1 x 2) structure formed on the Si(105) surface that includes the existence of surface strain. It corrects the model developed from early observations of the facets of "hut" clusters grown on Si(001).

Journal Article↗

PubMed1996

Dynamical complexity in age-structured models of the transmission of the measles virus: epidemiological implications at high levels of vaccine uptake.

This article explores the effect of increasingly finely stratified age structure on the dynamical properties of deterministic metapopulation models of the transmission of the measles virus. The dynamical simplicity of earlier age-structured models is shown to break down once the age-specific force of infection is no longer assumed to be constant across all child age classes below 5 years of age. While the biennial epidemics characteristic of earlier models are still observed, additional higher period stable cycles arise and coexist with the biennial cycle. The existence of multiple stable limit cycles necessarily implies model sensitivity on initial conditions, and for certain parameter values, chaotic dynamics are observed. Using a novel parameterization of the magnitude of seasonal forcing we are also able to make more biologically relevant comparisons between the dynamics of age- and non-age-structured models than have hitherto been possible. The epidemiological significance of these results is discussed, and we demonstrate that perturbations of the kind produced by intensive vaccination programs can shift transmission dynamics between biennial and triennial cycles. The possible implications of this work for studies of intermittency and infection persistence are also considered.

Adolescent↗

PubMed2003

The cytochrome c3-[Fe]-hydrogenase electron-transfer complex: structural model by NMR restrained docking.

Cytochrome c(3) (M(r) 13000) is a low redox potential cytochrome specific of the anaerobic metabolism in sulfate-reducing bacteria. This tetrahemic cytochrome is an intermediate between the [Fe]-hydrogenase and the cytochrome Hmc in Desulfovibrio vulgaris Hildenborough strain. The present work describes the structural model of the cytochrome c(3)-[Fe]-hydrogenase complex obtained by nuclear magnetic resonance restrained docking. This model connects the distal cluster of the [Fe]-hydrogenase to heme 4 of the cytochrome, the same heme found in the interaction with cytochrome Hmc. This result gives evidence that cytochrome c(3) is an electron shuttle between the periplasmic hydrogenase and the Hmc membrane-bound complex.

Cytochrome c Group↗

PubMed1999

A structural model for phosphorylation control of Dictyostelium myosin II thick filament assembly.

Myosin II thick filament assembly in Dictyostelium is regulated by phosphorylation at three threonines in the tail region of the molecule. Converting these three threonines to aspartates (3 x Asp myosin II), which mimics the phosphorylated state, inhibits filament assembly in vitro, and 3 x Asp myosin II fails to rescue myosin II-null phenotypes. Here we report a suppressor screen of Dictyostelium myosin II-null cells containing 3 x Asp myosin II, which reveals a 21-kD region in the tail that is critical for the phosphorylation control. These data, combined with new structural evidence from electron microscopy and sequence analyses, provide evidence that thick filament assembly control involves the folding of myosin II into a bent monomer, which is unable to incorporate into thick filaments. The data are consistent with a structural model for the bent monomer in which two specific regions of the tail interact to form an antiparallel tetrameric coiled-coil structure.

Actin Cytoskeleton↗

PubMed2006

A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG-CoA lyase.

3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and leucine metabolism. The disease is caused by mutations in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL). To date 26 different mutations have been described. A (betaalpha)(8) TIM barrel structure has been proposed for the protein, and almost all missense mutations identified so far localize in the beta sheets that define the inside cavity. We report an Italian patient who bears homozygously a novel HL mutation, c.608G > A (p. G203E) in beta sheet six. A structural model of the mutated protein suggests that glutamic acid 203 impedes catalysis by blocking the entrance to the inner cavity of the enzyme. Loss of functionality has been confirmed in expression studies in E. coli, which demonstrate that the G203E mutation completely abolishes enzyme activity. Beta sheet six and beta sheet two are the two protein regions that accumulate most missense mutations, indicating their importance in enzyme functionality. A model for the mechanism of enzyme function is proposed.

Amino Acid Metabolism, Inborn Errors↗

PubMed2006

A structural model of 20S immunoproteasomes: effect of LMP2 codon 60 polymorphism on expression, activity, intracellular localisation and insight into the regulatory mechanisms.

The immunoproteasome subunit low molecular weight protein 2 (LMP2) codon 60 polymorphism has been associated with autoimmune diseases. It has also been demonstrated to influence susceptibility to TNF-alpha-induced apoptosis in blood cells and proteasome activity in aged human brain. In the present study, an in silico model of immunoproteasome was used to examine the effect of the R60H polymorphism in the LMP2 subunit. The investigation of immunoproteasome expression, activity and intracellular localisation in an in vitro cellular model, namely lymphoblastoid cell lines, showed no major variations in functionality and amount, while a significant difference in antibody affinity was apparent. These data were integrated with previous results obtained in different tissues and combined with a structural model of the LMP2 polymorphism. Accordingly, we identified three prospective mechanisms that could explain the biological data for the polymorphism, such as modulation of the binding affinity of a putative non-catalytic modifier site on the external surface of the immunoproteasome core, or the modification of any channel between alpha and beta rings.

Antibodies, Monoclonal↗

PubMed2006

Advances in homology protein structure modeling.

Homology modeling plays a central role in determining protein structure in the structural genomics project. The importance of homology modeling has been steadily increasing because of the large gap that exists between the overwhelming number of available protein sequences and experimentally solved protein structures, and also, more importantly, because of the increasing reliability and accuracy of the method. In fact, a protein sequence with over 30% identity to a known structure can often be predicted with an accuracy equivalent to a low-resolution X-ray structure. The recent advances in homology modeling, especially in detecting distant homologues, aligning sequences with template structures, modeling of loops and side chains, as well as detecting errors in a model, have contributed to reliable prediction of protein structure, which was not possible even several years ago. The ongoing efforts in solving protein structures, which can be time-consuming and often difficult, will continue to spur the development of a host of new computational methods that can fill in the gap and further contribute to understanding the relationship between protein structure and function.

Animals↗

PubMed2002

The crystal structure of the hexadeca-heme cytochrome Hmc and a structural model of its complex with cytochrome c(3).

Sulfate-reducing bacteria contain a variety of multi-heme c-type cytochromes. The cytochrome of highest molecular weight (Hmc) contains 16 heme groups and is part of a transmembrane complex involved in the sulfate respiration pathway. We present the 2.42 A resolution crystal structure of the Desulfovibrio vulgaris Hildenborough cytochrome Hmc and a structural model of the complex with its physiological electron transfer partner, cytochrome c(3), obtained by NMR restrained soft-docking calculations. The Hmc is composed of three domains, which exist independently in different sulfate-reducing species, namely cytochrome c(3), cytochrome c(7), and Hcc. The complex involves the last heme at the C-terminal region of the V-shaped Hmc and heme 4 of cytochrome c(3), and represents an example for specific cytochrome-cytochrome interaction.

Crystallography, X-Ray↗

PubMed2007

The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models.

Atypical hemolytic uremic syndrome (aHUS) is a disease of hemolytic anemia, thrombocytopenia, and renal failure associated with defective alternative pathway (AP) complement control. Previously, we presented a database (www.FH-HUS.org) focusing on aHUS mutations in the Factor H gene (CFH). Here, new aHUS mutations are reported for the complement regulatory proteins Factor H (FH), Factor I (FI), and membrane cofactor protein (MCP). Additional mutations or polymorphisms within CFH have been associated with membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). Accordingly, the database now includes substitutions that predispose to aHUS, MPGN, and AMD. For this, structural models for the domains in MCP and FI were developed using homology modeling. With this new database, patients with mutations in more than one gene can be displayed and interpreted in a coherent manner. The database also includes SNP polymorphisms in CFH, MCP, and IF. There are now a total of 167 genetic alterations, including 100 in CFH, 43 in MCP, and 24 in IF. The mutations characterize clinical outcomes that vary from several AMD-associated polymorphisms to those associated with aHUS, MPGN, or FI deficiency. A consensus short complement regulator (SCR) domain structure facilitated the interpretations of aHUS mutations. Specific locations within this consensus domain often correlate with the occurrence of clinical phenotypes. The AMD Tyr402His polymorphism is structurally located at a hotspot for several aHUS mutations. The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches.

Amino Acid Sequence↗

PubMedDate not supplied

Nonparametric block-structured modeling of rat lung mechanics.

The quasistatic and dynamic pressure volume characteristics of the lungs were measured in five anesthetized, paralyzed open-chest rats. Psuedo-random volume perturbations over a frequency range of 0.25 to 25 Hz and having peak-peak amplitudes of 1 to 4 ml were applied after the lungs were allowed to expire against 0.2, 0.4, 0.6, and 0.8 kPa positive end-expiratory pressure (PEEP). The lung mechanics were partitioned in two ways: a linear dynamic block followed by a static nonlinearity (Wiener model) and a static nonlinearity ahead of a linear dynamic block (Hammerstein model). It was found that a Hammerstein model featuring a third-order polynomial static nonlinearity and a linear impulse response function of 1-sec duration accounted for the greatest amount of the output variance (98.8 +/- 0.6%, mean +/- SD from perturbations of 4 ml amplitude and PEEP = 0.8 kPa). The static nonlinear behavior matched the measured quasistatic pressure volume behavior obtained at the same amplitude and at the same level of PEEP, provided that all direct current gain of the model was located within the static nonlinearity. Under these conditions, the linear resistance was inversely dependent on the PEEP, whereas little PEEP or amplitude dependence of the linear compartment elastance was observed. Thus, of the two block-structured models tested, the Hammerstein model accounted better for the large amplitude nonlinear mechanical behavior. However, neither model could account for the dependence of the linear block resistance on PEEP.

Animals↗

PubMed1998

Structural model of the catalytic domain of an enzyme with cell adhesion activity: human vascular adhesion protein-1 (HVAP-1) D4 domain is an amine oxidase.

Human vascular adhesion protein-1 (HVAP-1) is a multifunctional protein having at least two different cellular roles, functioning both as a lymphocyte-endothelial cell adhesion protein and as an enzyme with monoamine oxidase activity. HVAP-1 is a 180 kDa homodimeric glycoprotein consisting of a membrane-spanning domain and three predicted extracellular copper-containing amine oxidase domains. In HVAP-1 the extracellular domains are composed of a large domain D4, containing the active site and forming the interface of the dimer, while the smaller D2 and D3 domains surround the D4 dimer near the entrance to the active site. The structural model of the catalytic D4 domain of HVAP-1 reveals that all components necessary for enzymatic monoamine oxidase activity are indeed present within the HVAP-1 and pinpoints residues that may be key to substrate entry through a channel to the active site and residues likely to be involved in substrate specificity as well as structural features critical to dimer formation. Proper glycosylation is required for the cell adhesion function of HVAP-1 and the predicted location of the sugar units at the solvent-exposed surface suits this function well.

Amine Oxidase (Copper-Containing)↗