bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Case for Autonomy‐Facilitating Education
Authors: Brighouse Harry 
Published: October 2003

Abstract
The first potentially powerful objection to school choice is that it might efface the right a child has to personal autonomy. This chapter argues for the right to an autonomy‐facilitating education on the child‐centred grounds that it is highly instrumental for individual flourishing. It also explores the educational requirements of the liberal legitimacy, which dovetail with the demands of an autonomy‐facilitating education. It contrasts these requirements with Amy Gutmann's curricular proposals.
Objections to Autonomy‐Facilitating Education
Authors: Brighouse Harry 
Published: October 2003

AbstractResponds to a series of objections to the argument for autonomy‐facilitating education, including objections from parental rights (put by Charles Fried), from religious freedom, from cultural rights, and from neutrality. It discusses further objections, which take the need for autonomy seriously, from William Galston and Shelley Burtt. It contains a detailed discussion of the Yoder versus Wisconsin case, in which Old Order Amish parents successfully claimed the right to withdraw their children from any form of schooling at the age of 14.
The Case for Educational Equality
Authors: Brighouse Harry 
Published: October 2003

AbstractThe second potential argument against choice is grounded in the value of educational equality. This chapter establishes the case for the principle of educational equality, which nests in the general value of equality of opportunity. It develops the principle to show what it implies concerning what resources should be devoted to students with disabilities and what the implications are for inclusion, and contrasts it with conceptions of educational equality grounded in multiculturalism.
Social Justice and Existing School Choice Programmes
Authors: Brighouse Harry 
Published: October 2003

AbstractLooks in detail at two existing school choice programmes, the Milwaukee Parental Choice Program, which distributes school vouchers to low‐income families, and the national choice program that has been in operation since 1988 in the UK. It evaluates them according to the criteria of justice elaborated in the previous chapters (the principle of autonomy and the principle of educational equality), showing that neither of them does well with respect to those criteria. The purpose is to identify what sorts of mechanisms cause them to do badly, and to illustrate that it is not choice but other features of the schemes that are to blame.
Protein self‐association in solution: The bovine β ‐lactoglobulin dimer and octamer
Authors: Gottschalk Michael , Nilsson Hanna , Roos Helena , Halle Bertil 
Published: October 2003

AbstractWe have used proton magnetic relaxation dispersion (MRD) to study the self‐association of bovine β‐lactoglobulin variant A (BLG‐A) as a function of temperature at pH 4.7 (dimer–octamer equilibrium) and as a function of NaCl concentration at pH 2.5 (monomer–dimer equilibrium). The MRD method identifies coexisting oligomers from their rotational correlation times and determines their relative populations from the associated dispersion amplitudes. From MRD‐derived correlation times and hydrodynamic model calculations, we confirm that BLG‐A dimers associate to octamers below room temperature. The tendency for BLG‐A dimers to assemble into octamers is found to be considerably weaker than in previous light scattering studies in the presence of buffer salt. At pH 2.5, the MRD data are consistent with an essentially complete transition from monomers in the absence of salt to dimers in 1 M NaCl. Because of an interfering relaxation dispersion from nanosecond water exchange, we cannot determine the oligomer populations at intermediate salt concentrations. This nanosecond dispersion may reflect intersite exchange of water molecules trapped inside the large binding cavity of BLG‐A.
H‐bonding mediates polarization of peptide groups in folded proteins
Authors: Juranić Nenad , Macura Slobodan , Prendergast Franklyn G. 
Published: October 2003

AbstractThe carbon‐nitrogen J‐couplings in the hydrogen bonding chains of proteins show that H‐bonding mediates peptide‐group polarization, which results in the general reduction of peptide‐group polarity of folded proteins in solution. The net effect is to make large regions of protein secondary structure, especially β‐sheets, intrinsically more hydrophobic, contributing thereby to overall stability of the tertiary structure.
Free‐energy landscape of a chameleon sequence in explicit water and its inherent α/β bifacial property
Authors: Ikeda Kazuyoshi , Higo Junichi 
Published: October 2003

AbstractA sequence in yeast MATα2/MCM1/DNA complex that folds into α‐helix or β‐hairpin depending on the surroundings has been known as “chameleon” sequence. We obtained the free‐energy landscape of this sequence by using a generalized‐ensemble method, multicanonical molecular dynamics simulation, to sample the conformational space. The system was expressed with an all‐atom model in explicit water, and the initial conformation for the simulation was a random one. The free‐energy landscape demonstrated that this sequence inherently has an ability to form either α or β structure: The conformational distribution in the landscape consisted of two α‐helical clusters with different packing patterns of hydrophobic residues, and four β‐hairpin clusters with different strand–strand interaction patterns. Narrow pathways connecting the clusters were found, and analysis on the pathways showed that a compact structure formed at the N‐terminal root of the chameleon sequence controls the cluster‐cluster transitions. The free‐energy landscape indicates that a small conditional change induces α‐β transitions. Additional unfolding simulations done with replacing amino acids showed that the chameleon sequence has an advantage to form an α‐helix. Current study may be useful to understand the mechanism of diseases resulting from abnormal chain folding, such as amyloid disease.
Initial structural and dynamic characterization of the M2 protein transmembrane and amphipathic helices in lipid bilayers
Authors: Tian Changlin , Gao Philip Fei , Pinto Lawrence H. , Lamb Robert A. , Cross Timothy A. 
Published: October 2003

AbstractAmphipathic helices in membrane proteins that interact with the hydrophobic/hydrophilic interface of the lipid bilayer have been difficult to structurally characterize. Here, the backbone structure and orientation of an amphipathic helix in the full‐length M2 protein from influenza A virus has been characterized. The protein has been studied in hydrated DMPC/DMPG lipid bilayers above the gel to liquid‐crystalline phase transition temperature by solid‐state NMR spectroscopy. Characteristic PISA (Polar Index Slant Angle) wheels reflecting helical wheels have been observed in uniformly aligned bilayer preparations of both uniformly 15N labeled and amino acid specific labeled M2 samples. Hydrogen/deuterium exchange studies have shown the very slow exchange of some residues in the amphipathic helix and more rapid exchange for the transmembrane helix. These latter results clearly suggest the presence of an aqueous pore. A variation in exchange rate about the transmembrane helical axis provides additional support for this claim and suggests that motions occur about the helical axes in this tetramer to expose the entire backbone to the pore.
Identification of transglutaminase‐mediated deamidation sites in a recombinant α‐gliadin by advanced mass‐spectrometric methodologies
Authors: Mazzeo Maria Fiorella , De Giulio Beatrice , Senger Stefania , Rossi Mauro , Malorni Antonio , Siciliano Rosa Anna 
Published: October 2003

AbstractCeliac disease is a permanent immune‐mediated food intolerance triggered by ingestion of wheat gliadins in genetically susceptible individuals. It has been reported that tissue transglutaminase plays an important role in the onset of celiac disease by converting specific glutamine residues within gliadin fragments into glutamic acid residues. This process increases binding affinity of gliadin peptides to HLA‐DQ2/DQ8 molecules, thus enhancing the immune response. The aim of the present study was to achieve a detailed structural characterization of modifications induced by transglutaminase on gliadin peptides. Therefore, structural analyses were carried out on a recombinant α‐gliadin and on a panel of 26 synthetic peptides, overlapping the complete protein sequence. Modified glutamine residues were identified by means of advanced mass‐spectrometric methodologies on the basis of MALDI‐TOF‐MS and tandem mass spectrometry. Results led to the identification of 19 of 94 glutamine residues present in the recombinant α‐gliadin, which were converted into glutamic acid residues by a transglutaminase‐mediated reaction. This allowed us to achieve a global view of the modifications induced by the enzyme on this protein. Furthermore, results gathered could likely be utilized as relevant information for a better understanding of processes leading to T‐cell recognition of gliadin peptides involved in celiac disease.
Allosteric transition pathways in the lactose repressor protein core domains: Asymmetric motions in a homodimer
Authors: Flynn Terence C. , Swint‐Kruse Liskin , Kong Yifei , Booth Christopher , Matthews Kathleen S. , Ma Jianpeng 
Published: October 2003

AbstractThe crystal structures of lactose repressor protein (LacI) provide static endpoint views of the allosteric transition between DNA‐ and IPTG‐bound states. To obtain an atom‐by‐atom description of the pathway between these two conformations, motions were simulated with targeted molecular dynamics (TMD). Strikingly, this homodimer exhibited asymmetric dynamics. All asymmetries observed in this simulation are reproducible and can begin on either of the two monomers. Asymmetry in the simulation originates around D149 and was traced back to the pre‐TMD equilibrations of both conformations. In particular, hydrogen bonds between D149 and S193 adopt a variety of configurations during repetitions of this process. Changes in this region propagate through the structure via noncovalent interactions of three interconnected pathways. The changes of pathway 1 occur first on one monomer. Alterations move from the inducer‐binding pocket, through the N‐subdomain β‐sheet, to a hydrophobic cluster at the top of this region and then to the same cluster on the second monomer. These motions result in changes at (1) side chains that form an interface with the DNA‐binding domains and (2) K84 and K84', which participate in the monomer–monomer interface. Pathway 2 reflects consequent reorganization across this subunit interface, most notably formation of a H74‐H74rsquo; π‐stacking intermediate. Pathway 3 extends from the rear of the inducer‐binding pocket, across a hydrogen‐bond network at the bottom of the pocket, and transverses the monomer–monomer interface via changes in H74 and H74rsquo;. In general, intermediates detected in this study are not apparent in the crystal structures. Observations from the simulations are in good agreement with biochemical data and provide a spatial and sequential framework for interpreting existing genetic data.
High‐resolution crystal structures of ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure‐based design of ribonucleolytic inhibitors
Authors: Leonidas Demetres D. , Chavali Gayatri B. , Oikonomakos Nikos G. , Chrysina Evangelia D. , Kosmopoulou Magda N. , Vlassi Metaxia , Frankling Claire , Acharya K. Ravi 
Published: October 2003

AbstractThe crystal structures of bovine pancreatic ribonuclease A (RNase A) in complex with 3′,5′‐ADP, 2′,5′‐ADP, 5′‐ADP, U‐2′‐p and U‐3′‐p have been determined at high resolution. The structures reveal that each inhibitor binds differently in the RNase A active site by anchoring a phosphate group in subsite P1. The most potent inhibitor of all five, 5′‐ADP (Ki = 1.2 μM), adopts a syn conformation (in contrast to 3′,5′‐ADP and 2′,5′‐ADP, which adopt an anti), and it is the β‐ rather than the α‐phosphate group that binds to P1. 3′,5′‐ADP binds with the 5′‐phosphate group in P1 and the adenosine in the B2 pocket. Two different binding modes are observed in the two RNase A molecules of the asymmetric unit for 2′,5′‐ADP. This inhibitor binds with either the 3′ or the 5′ phosphate groups in subsite P1, and in each case, the adenosine binds in two different positions within the B2 subsite. The two uridilyl inhibitors bind similarly with the uridine moiety in the B1 subsite but the placement of a different phosphate group in P1 (2′ versus 3′) has significant implications on their potency against RNase A. Comparative structural analysis of the RNase A, eosinophil‐derived neurotoxin (EDN), eosinophil cationic protein (ECP), and human angiogenin (Ang) complexes with these and other phosphonucleotide inhibitors provides a wealth of information for structure‐based design of inhibitors specific for each RNase. These inhibitors could be developed to therapeutic agents that could control the biological activities of EDN, ECP, and ANG, which play key roles in human pathologies.
Multiple structural alignment by secondary structures: Algorithm and applications
Authors: Dror Oranit , Benyamini Hadar , Nussinov Ruth , Wolfson Haim J. 
Published: October 2003

AbstractWe present MASS (Multiple Alignment by Secondary Structures), a novel highly efficient method for structural alignment of multiple protein molecules and detection of common structural motifs. MASS is based on a two‐level alignment, using both secondary structure and atomic representation. Utilizing secondary structure information aids in filtering out noisy solutions and achieves efficiency and robustness. Currently, only a few methods are available for addressing the multiple structural alignment task. In addition to using secondary structure information, the advantage of MASS as compared to these methods is that it is a combination of several important characteristics: (1) While most existing methods are based on series of pairwise comparisons, and thus might miss optimal global solutions, MASS is truly multiple, considering all the molecules simultaneously; (2) MASS is sequence order‐independent and thus capable of detecting nontopological structural motifs; (3) MASS is able to detect not only structural motifs, shared by all input molecules, but also motifs shared only by subsets of the molecules. Here, we show the application of MASS to various protein ensembles. We demonstrate its ability to handle a large number (order of tens) of molecules, to detect nontopological motifs and to find biologically meaningful alignments within nonpredefined subsets of the input. In particular, we show how by using conserved structural motifs, one can guide protein–protein docking, which is a notoriously difficult problem. MASS is freely available at http://bioinfo3d.cs.tau.ac.il/MASS/.
On the properties and sequence context of structurally ambivalent fragments in proteins
Authors: Kuznetsov Igor B. , Rackovsky S. 
Published: October 2003

AbstractThe goal of this work is to characterize structurally ambivalent fragments in proteins. We have searched the Protein Data Bank and identified all structurally ambivalent peptides (SAPs) of length five or greater that exist in two different backbone conformations. The SAPs were classified in five distinct categories based on their structure. We propose a novel index that provides a quantitative measure of conformational variability of a sequence fragment. It measures the context‐dependent width of the distribution of (ϕ,ξ) dihedral angles associated with each amino acid type. This index was used to analyze the local structural propensity of both SAPs and the sequence fragments contiguous to them. We also analyzed type‐specific amino acid composition, solvent accessibility, and overall structural properties of SAPs and their sequence context. We show that each type of SAP has an unusual, type‐specific amino acid composition and, as a result, simultaneous intrinsic preferences for two distinct types of backbone conformation. All types of SAPs have lower sequence complexity than average. Fragments that adopt helical conformation in one protein and sheet conformation in another have the lowest sequence complexity and are sampled from a relatively limited repertoire of possible residue combinations. A statistically significant difference between two distinct conformations of the same SAP is observed not only in the overall structural properties of proteins harboring the SAP but also in the properties of its flanking regions and in the pattern of solvent accessibility. These results have implications for protein design and structure prediction.
Revisiting the Ramachandran plot: Hard‐sphere repulsion, electrostatics, and H‐bonding in the α‐helix
Authors: Ho Bosco K. , Thomas Annick , Brasseur Robert 
Published: October 2003

AbstractWhat determines the shape of the allowed regions in the Ramachandran plot? Although Ramachandran explained these regions in terms of 1–4 hard‐sphere repulsions, there are discrepancies with the data where, in particular, the αR, αL, and β‐strand regions are diagonal. The αR‐region also varies along the α‐helix where it is constrained at the center and the amino terminus but diffuse at the carboxyl terminus. By analyzing a high‐resolution database of protein structures, we find that certain 1–4 hard‐sphere repulsions in the standard steric map of Ramachandran do not affect the statistical distributions. By ignoring these steric clashes (N···Hi+1 and Oi−1···C), we identify a revised set of steric clashes (Cβ···O, Oi−1···Ni+1, Cβ···Ni+1, Oi−1···Cβ, and Oi−1···O) that produce a better match with the data. We also find that the strictly forbidden region in the Ramachandran plot is excluded by multiple steric clashes, whereas the outlier region is excluded by only one significant steric clash. However, steric clashes alone do not account for the diagonal regions. Using electrostatics to analyze the conformational dependence of specific interatomic interactions, we find that the diagonal shape of the αR and αL‐regions also depends on the optimization of the N···Hi+1 and Oi−1···C interactions, and the diagonal β‐strand region is due to the alignment of the CO and NH dipoles. Finally, we reproduce the variation of the Ramachandran plot along the α‐helix in a simple model that uses only H‐bonding constraints. This allows us to rationalize the difference between the amino terminus and the carboxyl terminus of the α‐helix in terms of backbone entropy.
Recombinant extracellular domain of the three major subunits of GABAA receptor show comparable secondary structure and benzodiazepine binding properties
Authors: Shi Haifeng , Tsang Shui Ying , Tse Man Kit , Xu Zhiwen , Xue Hong 
Published: October 2003

AbstractThe three most widely expressed subunits of the GABAA receptor are α1, β2, and γ2 subunits, and the major isoform in the human brain is a pentameric receptor composed of 2α12β21γ2. Previously, we overexpressed the extracellular domain Q28‐R248 of GABAA receptor α1 subunit. In the present study, the homologous extracellular domains Q25‐G243 of GABAA receptor β2 subunit and Q40‐G273 of γ2 subunit were also obtained through overexpression in Escherichia coli. Successful production of recombinant β2 and γ2 subunit receptor protein domains facilitates the comparison of structural and functional properties of the three subunits. To this end, the secondary structures of the three fragments were measured using CD spectroscopy and the β‐strand contents calculated to be >30%, indicating a β‐rich structure for all three fragments. In addition, the benzodiazepine (BZ)‐binding affinity of the recombinant fragments were measured using fluorescence polarization to be 2.16 μM, 3.63 μM, and 1.34 μM for the α1, β2, and γ2 subunit fragments, respectively, indicating that all three homomeric assemblies, including that of the β2 subunit, generally not associated with BZ binding, can bind BZ in the micromolar range. The finding that the BZ binding affinity of these recombinant domains was highest for the γ2 subunit and lowest for the β2 subunit is consistent with results from previous binding studies using hetero‐oligomeric receptors. The present results exemplify the effective approach to characterize and compare the three major subunits of the GABAA receptor, for two of which the overexpression in E. coli is reported for the first time.
Soluble mimics of a chemokine receptor: Chemokine binding by receptor elements juxtaposed on a soluble scaffold
Authors: Datta Amita , Stone Martin J. 
Published: October 2003

AbstractDespite the broad biological importance of G protein–coupled receptors (GPCRs), ligand recognition by GPCRs remains poorly understood. To explore the roles of GPCR extracellular elements in ligand binding and to provide a tractable system for structural analyses of GPCR/ligand interactions, we have developed a soluble protein that mimics ligand recognition by a GPCR. This receptor analog, dubbed CROSS5, consists of the N‐terminal and third extracellular loop regions of CC chemokine receptor 3 (CCR3) displayed on the surface of a small soluble protein, the B1 domain of Streptococcal protein G. CROSS5 binds to the CCR3 ligand eotaxin with a dissociation equilibrium constant of 2.9 ± 0.8 μM and competes with CCR3 for eotaxin binding. Control proteins indicate that juxtaposition of both CCR3 elements is required for optimal binding to eotaxin. Moreover, the affinities of CROSS5 for a series of eotaxin mutants are highly correlated with the apparent affinities of CCR3 for the same mutants, demonstrating that CROSS5 uses many of the same interactions as does the native receptor. The strategy used to develop CROSS5 could be applied to many other GPCRs, with a variety of potential applications.
Solution structure and function of an essential CMP kinase of Streptococcus pneumoniae
Authors: Yu Liping , Mack Jamey , Hajduk Philip J. , Kakavas Steve J. , Saiki Anne Y.C. , Lerner Claude G. , Olejniczak Edward T. 
Published: October 2003

AbstractStreptococcus pneumoniae is a major human pathogen that causes high mortality and morbidity and has developed resistance to many antibiotics. We show that the gene product from SP1603, identified from S. pneumoniae TIGR4, is a CMP kinase that is essential for bacterial growth. It represents an attractive drug target for the development of a novel antibiotic to overcome the problems of drug resistance development for this organism. Here we describe the three‐dimensional solution structure of the S. pneumoniae CMP kinase as determined by NMR spectroscopy. The structure consists of eight α‐helices and two β‐sheets that fold into the classical core domain, the substrate‐binding domain, and the LID domain. The three domains of the protein pack together to form a central cavity for substrate‐binding and enzymatic catalysis. The S. pneumoniae CMP kinase resembles the fold of the Escherichia coli homolog. An insertion of one residue is observed at the β‐turn in the substrate‐binding domain of the S. pneumoniae CMP kinase when compared with the E. coli homolog. Chemical shift perturbations caused by the binding of CMP, CDP, and ATP revealed that CMP or CDP binds to the junction between the core and substrate‐binding domains, whereas ATP binds to the junction between the core and LID domains. From NMR relaxation studies, we determined that the loops in the LID domain are highly mobile. These mobile loops could aid in the closing/opening of the LID domain during enzyme catalysis.