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At least 379 records · Page 21Linked to original sources
PubMed1999

A simple structured model for continuous production of a hybrid antibiotic by Streptomyces lividans pellets in a fluidized-bed bioreactor.

A simple structured model is developed for the description of the experiments of continuous production of a hybrid antibiotic by Streptomyces lividans TK21 pellets in a fluidized-bed reactor. The model is based on the effect of internal and external phosphate concentrations on antibiotic production during cyclic feeding. These concentrations can be calculated on the basis of the equations postulated by the model. The model also considers the cell growth, reflected in changes of the pellet size along the culture. The model parameters are evaluated sequentially by performing experiments at different operational conditions. The validity of the model and its corresponding parameters is corroborated further by the satisfactory modeling of the bioreactor operation during an extended period of time at various operation conditions.

Anti-Bacterial Agents↗
PubMed1992

A structural model examining the relationship between physical child abuse, sexual victimization, and marijuana/hashish use in delinquent youth: a longitudinal study.

A structural model of the relationships among physical abuse and sexual victimization experiences, marijuana/hashish use (measured by self-report and urine test data) and self-reported delinquent behavior (theft crimes, index offenses, crimes against persons, drug sales and total delinquency) over time was tested in a longitudinal study of juvenile detainees. The hypothesized model was supported by the data. Theoretical, research and policy implications of the results are drawn.

Adolescent↗
PubMed1999

Structural models of the KtrB, TrkH, and Trk1,2 symporters based on the structure of the KcsA K(+) channel.

Three-dimensional computer modeling is used to further investigate the hypothesis forwarded in the accompanying paper of an evolutionary relationship between four related families of K(+) sympoter proteins and the superfamily of K(+) channel proteins. Atomic-scale models are developed for the transmembrane regions of one member from each of the three more distinct symporter families, i.e., a TrkH protein from Escherichia coli, a KtrB protein from Aquifex aeolicus, and a Trk1,2 protein from Schizosaccharomyces pombe. The portions of the four consecutive M1-P-M2 motifs in the symporters that can be aligned with K(+) channel sequences are modeled directly from the recently determined crystal structure of the KcsA K(+) channel from Streptomyces lividans. The remaining portions are developed using our previously accumulated theoretical modeling criteria and principles. Concurrently, the use of these criteria and principles is further supported by the now verified predictions of our previous K(+) channel modeling efforts and the degree to which they are satisfied by the known structure of the KcsA protein. Thus the observed ability of the portions of the symporter models derived from the KcsA crystal structure to also satisfy the theoretical modeling criteria provides additional support for an evolutionary link with K(+) channel proteins. Efforts to further satisfy the criteria and principles suggest that the symporter proteins from fungi and plants (i.e., Trk1,2 and HKT1) form dimeric and/or tetrameric complexes in the membrane. Furthermore, analysis of the atomic-scale models in relation to the sequence conservation within and between the protein families suggests structural details for previously proposed mechanisms for the linked symport of K(+) with Na(+) and H(+). Suggestions are also given for experiments to test these structures and hypotheses.

Amino Acid Sequence↗
PubMed1996

A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis.

HLA molecules associated with rheumatoid arthritis (RA) contain a discrete structural element known as the shared epitope, a set of conserved amino acid residues located on the alpha helical portion of the class II beta chain. Each of the different HLA molecules associated with RA contain the same shared epitope sequence, although they may vary markedly in other regions of the class II structure, which also determine peptide-class II interactions. Previous mutagenesis studies and structural modelling indicate that key polymorphic amino acid side chains within the shared epitope sequence are in locations likely to contact the T cell receptor (TCR) during the trimolecular activation reaction between the HLA-peptide complex and TCR. We have evaluated the potential structural basis for such shared epitope recognition by analysing detailed molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor from T cell clone EM025, specific for HLA-DR4 molecules which carry the shared epitope. A likely orientation for the trimolecular complex was deduced in which the EM025 alpha chain interacts with the DR alpha chain and the EM025 beta chain interacts with the DR beta chain; residues Q70 and R71 within the DR beta chain shared epitope region are positioned for hydrogen bond interactions directly with Q97 of the TCR beta CDR3 region, D30 of the TCR beta CDR1 region, and possibly N51 of the TCR beta CDR2 region, indicating a degree of specific selection and interaction which encompasses multiple TCR contacts. These findings suggest a structural basis for the genetic associations with the HLA shared epitope and the potential contribution of this region to oligoclonal T cell selection and expansion in RA.

Arthritis, Rheumatoid↗
PubMed2006

Improving the quality of protein structure models by selecting from alignment alternatives.

BACKGROUND: In the area of protein structure prediction, recently a lot of effort has gone into the development of Model Quality Assessment Programs (MQAPs). MQAPs distinguish high quality protein structure models from inferior models. Here, we propose a new method to use an MQAP to improve the quality of models. With a given target sequence and template structure, we construct a number of different alignments and corresponding models for the sequence. The quality of these models is scored with an MQAP and used to choose the most promising model. An SVM-based selection scheme is suggested for combining MQAP partial potentials, in order to optimize for improved model selection. RESULTS: The approach has been tested on a representative set of proteins. The ability of the method to improve models was validated by comparing the MQAP-selected structures to the native structures with the model quality evaluation program TM-score. Using the SVM-based model selection, a significant increase in model quality is obtained (as shown with a Wilcoxon signed rank test yielding p-values below 10(-15)). The average increase in TMscore is 0.016, the maximum observed increase in TM-score is 0.29. CONCLUSION: In template-based protein structure prediction alignment is known to be a bottleneck limiting the overall model quality. Here we show that a combination of systematic alignment variation and modern model scoring functions can significantly improve the quality of alignment-based models.

Computer Simulation↗
PubMed1989

A covariance structure model test of antecedents of adolescent alcohol misuse and a prevention effort.

As part of an alcohol misuse prevention evaluation, questionnaires were administered to 4,157 junior high school students to determine levels of alcohol misuse, exposure to peer use and misuse of alcohol, susceptibility to peer pressure, internal health locus of control, and self-esteem. A conceptual model of the antecedents of adolescent alcohol misuse and the effectiveness of a prevention effort was tested using covariance structure modeling techniques. The factor loadings for the model were all moderate to high, indicating that the observed variables served well as measurement instruments for the latent variables. The hypothesized structural relationships among the latent variables of alcohol misuse, exposure to peer use and misuse of alcohol, susceptibility to peer pressure, internal health locus of control, and self-esteem were supported by the data. The full model explained 45 percent of the variance in alcohol misuse in the analysis based on the total sample. The direct effect of the intervention on alcohol misuse was small but significant in the hypothesized direction. The direct effects of the intervention on susceptibility to peer pressure and internal health locus of control were not significant. The model was tested separately for groups of students who had high versus low scores on susceptibility to peer pressure in order to test the interaction between susceptibility to peer pressure and exposure to peer use and misuse of alcohol. The percentage of variance accounted for in alcohol misuse did not increase upon testing the model separately for students who had high versus low scores on susceptibility to peer pressure. Observed differences in the significance of the parameter estimates between the high and low susceptibility to peer pressure groups suggest that different approaches to the design and evaluation of substance abuse prevention programs may be necessary for different subgroups of students.

Alcoholism↗
PubMed2005

A structural model for unfolded proteins from residual dipolar couplings and small-angle x-ray scattering.

Natively unfolded proteins play key roles in normal and pathological biochemical processes. Despite their importance for function, this category of proteins remains beyond the reach of classical structural biology because of their inherent conformational heterogeneity. We present a description of the intrinsic conformational sampling of unfolded proteins based on residue-specific /Psi propensities from loop regions of a folded protein database and simple volume exclusion. This approach is used to propose a structural model of the 57-aa, natively disordered region of the nucleocapsid-binding domain of Sendai virus phosphoprotein. Structural ensembles obeying these simple rules of conformational sampling are used to simulate averaged residual dipolar couplings (RDCs) and small-angle x-ray scattering data. This protein is particularly informative because RDC data from the equally sized folded and unfolded domains both report on the unstructured region, allowing a quantitative analysis of the degree of order present in this part of the protein. Close agreement between experimental and simulated RDC and small-angle x-ray scattering data validates this simple model of conformational sampling, providing a precise description of local structure and dynamics and average dimensions of the ensemble of sampled structures. RDC data from two urea-unfolded systems are also closely reproduced. The demonstration that conformational behavior of unfolded proteins can be accurately predicted from the primary sequence by using a simple set of rules has important consequences for our understanding of the structure and dynamics of the unstructured state.

Models, Molecular↗
PubMed1992

Structured modeling of fish physiology.

The use of models in simulation and state estimation has proved useful in diverse applications, especially in industrial process control. The project presented here looked into the modeling of fish physiology for applications in fish physiology research and aquaculture. The models deal with gastric evacuation, metabolism, kidneys, gills, the cardiovascular system, and feeding behavior and are based on data from the literature. Model responses are mostly in accord with real responses in principle, but, as with most models of complex biological systems, the numerical accuracy is low in several cases. However, these structured models enable researchers to test hypotheses by altering the submodels and parameters.

Animals↗
PubMed1991

Structural modeling of mixed longitudinal and cross-sectional data.

In this paper we describe some mathematical and statistical models for dealing with changes over age. We concentrate specifically on the use of a structural equation modeling (SEM) approach (using computer programs like LISREL) to deal with issues of: (1) group differences in regression parameters, (2) differences in longitudinal and cross-sectional results, (3) differences due to longitudinal attrition, and (4) mixtures of these problems. To illustrate these ideas we use data from a previous study of hypertension and intellectual abilities (from Schultz, Elias, Robbins, Streeten, and Blakeman, 1986).

Adult↗
PubMed2002

Crystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase.

Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. The enzyme is found in abundance in the livers of all vertebrates. Recombinant rat liver GAMT has been crystallized with S-adenosylhomocysteine (SAH), and the crystal structure has been determined at 2.5 A resolution. The 36 amino acid residues at the N terminus were cleaved during the purification and the truncated enzyme was crystallized. The truncated enzyme forms a dimer, and each subunit contains one SAH molecule in the active site. Arg220 of the partner subunit forms a pair of hydrogen bonds with Asp134 at the guanidinoacetate-binding site. On the basis of the crystal structure, site-directed mutagenesis on Asp134, and chemical modification and limited proteolysis studies, we propose a catalytic mechanism of this enzyme. The truncated GAMT dimer structure can be seen as a ternary complex of protein arginine methyltransferase (one subunit) complexed with a protein substrate (the partner subunit) and the product SAH. Therefore, this structure provides insight into the structure and catalysis of protein arginine methyltransferases.

Animals↗
PubMed1998

Structural model of phospholipid-reconstituted human transferrin receptor derived by electron microscopy.

BACKGROUND: The transferrin receptor (TfR) regulates the cellular uptake of serum iron. Although the TfR serves as a model system for endocytosis receptors, neither crystal structure analysis nor electron microscopy has yet revealed the molecular dimensions of the TfR. To derive the first molecular model, we analyzed purified, lipid-reconstituted human TfR by high-resolution electron microscopy. RESULTS: A structural model of phospholipid-reconstituted TfR was derived from 72 cryo-electron microscopic images. The TfR dimer consists of a large extracellular globular domain (6.4 x 7.5 x 10.5 nm) separated from the membrane by a thin molecular stalk (2.9 nm). A comparative protein sequence analysis suggests that the stalk corresponds to amino acid residues 89-126. Under phospholipid-reconstitution conditions, the human TfR not only integrates into vesicles, but also forms rosette-like structures called proteoparticles. Scanning transmission electron microscopy revealed an overall diameter of 31.5 nm and a molecular mass of 1669 +/- 26 kDa for the proteoparticles, corresponding to nine TfR dimers. The average mass of a single receptor dimer was determined as being 186 +/- 4 kDa. CONCLUSIONS: Proteoparticles resemble TfR exosomes that are expelled by sheep reticulocytes upon maturation. The structure of proteoparticles in vitro is thus interpreted as being the result of the TfR's strong self-association potential, which might facilitate the endosomal sequestration of the TfR away from other membrane proteins and its subsequent return to the cell surface within tubular structures. The stalk is assumed to facilitate the tight packing of receptor molecules in coated pits and recycling tubuli.

Animals↗
PubMed1994

The active site architecture of a short-chain dehydrogenase defined by site-directed mutagenesis and structure modeling.

A high-resolution crystal structure is not currently available for Drosophila alcohol dehydrogenase. A detailed three-dimensional model for this enzyme, based on the structure of 3 alpha,20 beta-hydroxysteroid dehydrogenase, has been generated by extensive computer modeling studies. Aspects of the model concerned with coenzyme binding have been tested by site-directed mutagenesis of residues Gly-14 to Ala, Gly-19 to Ala, Asp-38 to Ala, and Pro-214 to Ser. All enzymes have been characterized in terms of kinetic constants, relative stabilities to guanidinium chloride, and heat inactivation. The contribution of NAD binding to the stabilization of each of the enzymes was also measured. The results obtained with enzymes mutated at positions 14, 38, and 214 are in accordance with published data on Drosophila alcohol dehydrogenase and suggest interactions of these residues with the cofactor NAD. The introduction of a methyl group at residue Gly-19 abolished the ability of the enzyme to utilize NADP instead of NAD. This reflects a proximity of residue Gly-19 to the ribose ring of the bound cofactor. This result, coupled to the three-dimensional model built for Drosophila alcohol dehydrogenase, suggests a binding mechanism for the cofactor NAD different from that found for 3 alpha,20 beta-dehydroxysteroid dehydrogenase and similar to that found in the crystal structure of rat liver dihydropteridine reductase. The model of Drosophila alcohol dehydrogenase also enables many previous observations from chemical modification, sequence comparisons, site-directed mutagenesis, and limited proteolysis experiments to be placed into a structural context. An active site architecture is proposed involving a loop closure mechanism similar to that of lactate dehydrogenase.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed1990

Comparative fit indexes in structural models.

Normed and nonnormed fit indexes are frequently used as adjuncts to chi-square statistics for evaluating the fit of a structural model. A drawback of existing indexes is that they estimate no known population parameters. A new coefficient is proposed to summarize the relative reduction in the noncentrality parameters of two nested models. Two estimators of the coefficient yield new normed (CFI) and nonnormed (FI) fit indexes. CFI avoids the underestimation of fit often noted in small samples for Bentler and Bonett's (1980) normed fit index (NFI). FI is a linear function of Bentler and Bonett's non-normed fit index (NNFI) that avoids the extreme underestimation and overestimation often found in NNFI. Asymptotically, CFI, FI, NFI, and a new index developed by Bollen are equivalent measures of comparative fit, whereas NNFI measures relative fit by comparing noncentrality per degree of freedom. All of the indexes are generalized to permit use of Wald and Lagrange multiplier statistics. An example illustrates the behavior of these indexes under conditions of correct specification and misspecification. The new fit indexes perform very well at all sample sizes.

Humans↗
PubMed1999

Mechanical and structural model of fractal networks of fat crystals at low deformations.

Fat-crystal networks demonstrate viscoelastic behavior at very small deformations. A structural model of these networks is described and supported by polarized light and atomic-force microscopy. A mechanical model is described which allows the shear elastic modulus (G') of the system to be correlated with forces acting within the network. The fractal arrangement of the network at certain length scales is taken into consideration. It is assumed that the forces acting are due to van der Waals forces. The final expression for G' is related to the volume fraction of solid fat (Phi) via the mass fractal dimension (D) of the network, which agrees with the experimental verification of the scaling behavior of fat-crystal networks [S. S. Narine and A. G. Marangoni, Phys. Rev. E 59, 1908 (1999)]. G' was also found to be inversely proportional to the diameter of the primary particles (sigma approximately equal to 6 microm) within the network (microstructural elements) as well as to the diameter of the microstructures (xi approximately equal to 100 microm) and inversely proportional to the cube of the intermicrostructural element distance (d(0)). This formulation of the elastic modulus agrees well with experimental observations.

Journal Article↗
PubMed1998

A six-domain structural model for Escherichia coli translation initiation factor IF2. Characterisation of twelve surface epitopes.

The Escherichia coli translation initiation factor IF2 is a 97 kDa protein which interacts with the initiator fMet-tRNAfMet, GTP and the ribosomal subunits during initiation of protein biosynthesis. For structural and functional investigations of the factor, we have raised and characterised monoclonal antibodies against E. coli IF2. Twelve epitopes have been localised at the surface of the protein molecule by three different methods: Interactions of the monoclonal antibodies with nested deletion mutants of IF2, comparison of the relative location of the epitopes in a competition immunoassay and cross-reactivity analyses of the monoclonal antibodies towards IF2 from Salmonella typhimurium, Klebsiella oxytoca, Enterobacter cloacae, Proteus vulgaris, and Bacillus stearothermophilus. These data are combined with predicted secondary structure and discussed in relation to a six-domain structural model for IF2. The model describes IF2 as a slightly elongated molecule with a structurally compact C-terminal domain, a well-conserved central GTP-binding domain, and a highly charged, solvent exposed N-terminal with protruding alpha-helical structures.

Amino Acid Sequence↗
PubMed2002

Structure modeling of the chemokine receptor CCR5: implications for ligand binding and selectivity.

The G-protein coupled receptor CCR5 is the main co-receptor for macrophage-tropic HIV-1 strains. I have built a structural model of the chemokine receptor CCR5 and used it to explain the binding and selectivity of the antagonist TAK779. Models of the extracellular (EC) domains of CCR5 have been constructed and used to rationalize current biological data on the binding of HIV-1 and chemokines. Residues spanning the transmembrane region of CCR5 have been modeled after rhodopsin, and their functional significance examined using the evolutionary trace method. The receptor cavity shares six residues with CC-chemokine receptors CCR1 through CCR4, while seven residues are unique to CCR5. The contribution of these residues to ligand binding and selectivity is tested by molecular docking simulations of TAK779 to CCR1, CCR2, and CCR5. TAK779 binds to CCR5 in the cavity formed by helices 1, 2, 3, and 7 with additional interactions with helices 5 and 6. TAK779 did not dock to either CCR1 or CCR2. The results are consistent with current site-directed mutagenesis data and with the observed selectivity of TAK779 for CCR5 over CCR1 and CCR2. The specific residues responsible for the observed selectivity are identified. The four EC regions of CCR5 have been modeled using constrained simulated annealing simulations. Applied dihedral angle constraints are representative of the secondary structure propensities of these regions. Tertiary interactions, in the form of distance constraints, are generated from available epitope mapping data. Analysis of the 250 simulated structures provides new insights to the design of experiments aimed at determining residue-residue contacts across the EC domains and for mapping CC-chemokines on the surface of the EC domains.

Amides↗
PubMed1982

A structural model for maize zein proteins.

With the knowledge of the amino acid sequences of two maize zein proteins (apparent molecular weights of 19,000 and 22,000), a structural model is proposed for their molecular conformation. The circular dichroic spectrum taken in the 190-240 nm range for a zein protein mixture in methanol solution showed the zein secondary structure to be largely helical. The polar, hydrophobic, and turn characteristics of the zein residues, as well as the homologous repeat units in their primary sequences, suggested a structure with nine adjacent, topologically antiparallel helices clustered within a distorted cylinder. Polar residues distributed along the helical surfaces allowed intra- and intermolecular hydrogen bonding such that the zein molecules could be arranged in planes. The proposed glutamine-rich turns located between the helices and at the cylindrical caps would favor side chain interactions resulting in stacking of the molecular planes. Physical properties observed for the zein proteins are explained by the model.

Amino Acid Sequence↗