bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the amino acid contribution to the folding degree of proteins
Authors: Estrada Ernesto 
Published: February 2004

AbstractThe folding degree index (Estrada, Bioinformatics 2002;18:697–704) is extended to account for the contribution of amino acids to folding. First, the mathematical formalism for extending the folding degree index is presented. Then, the amino acid contributions to folding degree of several proteins are used to analyze its relation to secondary structure. The possibilities of using these contributions in helping or checking the assignation of secondary structure to amino acids are also introduced. The influence of external factors to the amino acids contribution to folding degree is studied through the temperature effect on ribonuclease A. Finally, the analysis of 3D protein similarity through the use of amino acid contributions to folding degree is studied by selecting a series of lysozymes. These results are compared to that obtained by sequence alignment (2D similarity) and 3D superposition of the structures, showing the uniqueness of the current approach. Proteins 2004;54:000–000. © 2004 Wiley‐Liss, Inc.
Identification of common structural features of binding sites in galactose‐specific proteins
Authors: Sujatha M.S. , Balaji Petety V. 
Published: February 2004

AbstractGalactose‐binding proteins characterize an important subgroup of sugar‐binding proteins that are involved in a variety of biological processes. Structural studies have shown that the Gal‐specific proteins encompass a diverse range of primary and tertiary structures. The binding sites for galactose also seem to vary in different protein‐galactose complexes. No common binding site features that are shared by the Gal‐specific proteins to achieve ligand specificity are so far known. With the assumption that common recognition principles will exist for common substrate recognition, the present study was undertaken to identify and characterize any unique galactose‐binding site signature by analyzing the three‐dimensional (3D) structures of 18 protein‐galactose complexes. These proteins belong to 7 nonhomologous families; thus, there is no sequence or structural similarity across the families. Within each family, the binding site residues and their relative distances were well conserved, but there were no similarities across families. A novel, yet simple, approach was adopted to characterize the binding site residues by representing their relative spatial dispositions in polar coordinates. A combination of the deduced geometrical features with the structural characteristics, such as solvent accessibility and secondary structure type, furnished a potential galactose‐binding site signature. The signature was evaluated by incorporation into the programCOTRANto search for potential galactose‐binding sites in proteins that share the samefoldas the known galactose‐binding proteins.COTRANis able to detect galactose‐binding sites with a very high specificity and sensitivity. The deduced galactose‐binding site signature is strongly validated and can be used to search for galactose‐binding sites in proteins. PROSITE‐type signature sequences have also been inferred for galectin and C‐type animal lectin‐likefoldfamilies of Gal‐binding proteins. Proteins 2004;55:44–65. © 2004 Wiley‐Liss, Inc.
Structural analysis of disease‐causing mutations in the P‐subfamily of forkhead transcription factors
Authors: Banerjee‐Basu Sharmila , Baxevanis Andreas D. 
Published: February 2004

AbstractMutations in a number of forkhead transcription factors are associated with the development of inherited diseases in humans. Two closely related genes, FOXP2 and FOXP3, are implicated in two completely different human disorders. A point mutation in the forkhead domain of FOXP2 (R553H) is responsible for a severe speech and language disorder, while a series of missense mutations distributed over the forkhead domain of FOXP3 cause a fatal disorder called IPEX, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. Homology model building techniques were used to generate atomic structures of FOXP2 and FOXP3, using the solution structures of the forkhead domain of the adipocyte‐transcription factor FREAC‐11 and AFX as templates. The impact of these disease‐causing missense mutations on the three‐dimensional structure, stability, and surface electrostatic charge distribution of the forkhead domains is examined here. The missense mutations R553H in FOXP2 and R397W in FOXP3 dramatically alter the electrostatic potentials of the molecular surface of their respective forkhead domains. Proteins 2004. © 2003 Wiley‐Liss, Inc.
Recovering the true targets of specific ligands by virtual screening of the protein data bank
Authors: Paul Nicodéme , Kellenberger Esther , Bret Guillaume , Müller Pascal , Rognan Didier 
Published: February 2004

AbstractThe Protein Data Bank (PDB) has been processed to extract a screening protein library (sc‐PDB) of 2148 entries. A knowledge‐based detection algorithm has been applied to 18,000 PDB files to find regular expressions corresponding to either protein, ions, co‐factors, solvent, or ligand atoms. The sc‐PDB database comprises high‐resolution X‐ray structures of proteins for which (i) a well‐defined active site exists, (ii) the bound‐ligand is a small molecular weight molecule. The database has been screened by an inverse docking tool derived from the GOLD program to recover the known target of four unrelated ligands. Both the database and the inverse screening procedures are accurate enough to rank the true target of the four investigated ligands among the top 1% scorers, with 70–100 fold enrichment with respect to random screening. Applying the proposed screening procedure to a small‐sized generic ligand was much less accurate suggesting that inverse screening shall be reserved to rather selective compounds. Proteins 2004;54:000–000. © 2004 Wiley‐Liss, Inc.
Trehalose–protein interaction in aqueous solution
Authors: Lins Roberto D. , Pereira Cristina S. , Hünenberger Philippe H. 
Published: February 2004

AbstractA variety of sugars are known to enhance the stability of biomaterials. Trehalose, a nonreducing disaccharide composed of two α, α(1 → 1)‐linked D‐glucopyranose units, appears to be one of the most effective protectants. Both in vivo and in vitro, trehalose protects biostructures such as proteins and membranes from damage due to dehydration, heat, or cold. However, despite the significant amount of experimental data on this disaccharide, no clear picture of the molecular mechanism responsible for its stabilizing properties has emerged yet. Three major hypotheses (water–trehalose hydrogen‐bond replacement, coating by a trapped water layer, and mechanical inhibition of the conformational fluctuations) have been proposed to explain the stabilizing effect of trehalose on proteins. To investigate the nature of protein–trehalose–water interactions in solution at the molecular level, two molecular dynamics simulations of the protein lysozyme in solution at room temperature have been carried out, one in the presence (about 0.5 M) and one in the absence of trehalose. The results show that the trehalose molecules cluster and move toward the protein, but neither completely expel water from the protein surface nor form hydrogen bonds with the protein. Furthermore, the coating by trehalose does not significantly reduce the conformational fluctuations of the protein compared to the trehalose‐free system. Based on these observations, a model is proposed for the interaction of trehalose molecules with a protein in moderately concentrated solutions, at room temperature and on the nanosecond timescale. Proteins 2004;55:177–186. © 2004 Wiley‐Liss, Inc.
Solution structure of the ubiquitin‐binding domain in Swa2p from Saccharomyces cerevisiae
Authors: Chim Nicholas , Gall Walter E. , Xiao Jing , Harris Mark P. , Graham Todd R. , Krezel Andrzej M. 
Published: February 2004

AbstractThe SWA2/AUX1 gene has been proposed to encode the Saccharomyces cerevisiae ortholog of mammalian auxilin. Swa2p is required for clathrin assembly/dissassembly in vivo, thereby implicating it in intracellular protein and lipid trafficking. While investigating the 287‐residue N‐terminal region of Swa2p, we found a single stably folded domain between residues 140 and 180. Using binding assays and structural analysis, we established this to be a ubiquitin‐associated (UBA) domain, unidentified by bioinformatics of the yeast genome. We determined the solution structure of this Swa2p domain and found a characteristic three‐helix UBA fold. Comparisons of structures of known UBA folds reveal that the position of the third helix is quite variable. This helix in Swa2p UBA contains a bulkier tyrosine in place of smaller residues found in other UBAs and cannot pack as close to the second helix. The molecular surface of Swa2p UBA has a mostly negative potential, with a single hydrophobic surface patch found also in the UBA domains of human protein, HHR23A. The presence of a UBA domain implicates Swa2p in novel roles involving ubiquitin and ubiquitinated substrates. We propose that Swa2p is a multifunctional protein capable of recognizing several proteins through its protein–protein recognition domains. Proteins 2004;54:000–000. © 2004 Wiley‐Liss, Inc.
Rapid protein–ligand docking using soft modes from molecular dynamics simulations to account for protein deformability: Binding of FK506 to FKBP
Authors: Zacharias Martin 
Published: February 2004

AbstractMost current docking methods to identify possible ligands and putative binding sites on a receptor molecule assume a rigid receptor structure to allow virtual screening of large ligand databases. However, binding of a ligand can lead to changes in the receptor protein conformation that are sterically necessary to accommodate a bound ligand. An approach is presented that allows relaxation of the protein conformation in precalculated soft flexible degrees of freedom during ligand–receptor docking. For the immunosuppressant FK506‐binding protein FKBP, the soft flexible modes are extracted as principal components of motion from a molecular dynamics simulation. A simple penalty function for deformations in the soft flexible mode is used to limit receptor protein deformations during docking that avoids a costly recalculation of the receptor energy by summing over all receptor atom pairs at each step. Rigid docking of the FK506 ligand binding to an unbound FKBP conformation failed to identify a geometry close to experiment as favorable binding site. In contrast, inclusion of the flexible soft modes during systematic docking runs selected a binding geometry close to experiment as lowest energy conformation. This has been achieved at a modest increase of computational cost compared to rigid docking. The approach could provide a computationally efficient way to approximately account for receptor flexibility during docking of large numbers of putative ligands and putative docking geometries. Proteins 2004;54:000–000. © 2004 Wiley‐Liss, Inc.
Conserved spatially interacting motifs of protein superfamilies: Application to fold recognition and function annotation of genome data
Authors: Bhaduri Anirban , Ravishankar R. , Sowdhamini R. 
Published: February 2004

AbstractLimitations in techniques for the elucidation of protein function have led to an increasing gap between the annotated proteins and those encoded in a genome. The functional selection and three‐dimensional structural constraints of proteins in nature often relate to the retention of significant sequence similarity between proteins of similar fold and function despite poor sequence identity. We identify spatially interacting conserved regions, or motifs, within protein superfamilies that are critical for structure and/or function. A search in sequence databases using these descriptors as additional constraints is an approach to identifying putative additional members of superfamilies. Such constrained searches have been tested against proteins of known structure to demonstrate high percentage specificity (93) with a low error rate of 0.0004. This approach has been compared with other sensitive sequence search methods (e.g., PSI‐BLAST, HMMsearch, and IMPALA). It has been extended to analyze the distribution of 11 superfamilies in 93 genomes, including the human genome. Proteins 2004;54:000–000. © 2004 Wiley‐Liss, Inc.
Extreme free energy of stabilization of Taq DNA polymerase
Authors: Schoeffler Allyn J. , Joubert Allison M. , Peng Fenggang , Khan Farheen , Liu Chin‐Chi , LiCata Vince J. 
Published: February 2004

AbstractWe have examined the chemical denaturations of the Klentaq and Klenow large‐fragment domains of the Type 1 DNA polymerases from Thermus aquaticus (Klentaq) and Escherichia coli (Klenow) under identical solution conditions in order to directly compare the stabilization energetics of the two proteins. The high temperature stability of Taq DNA polymerase is common knowledge, and is the basis of its use in the polymerase chain reaction. This study, however, is aimed at understanding the thermodynamic basis for this high‐temperature stability. Chemical denaturations with guanidine hydrochloride report a folding free energy (ΔG) for Klentaq that is over 20 kcal/mol more favorable than that for Klenow under the conditions examined. This difference between the stabilization free energies of a homologous mesophilic–thermophilic protein pair is significantly larger than generally observed. This is due in part to the fact that the stabilization free energy for Klentaq polymerase, at 27.5 kcal/mol, is one of the largest ever determined for a monomeric protein. Large differences in the chemical midpoints of the unfolding (Cm) and the dependences of the unfolding free energy on denaturant concentration in the transition region (m‐value) between the two proteins are also observed. Measurements of the sedimentation coefficients of the two proteins in the native and denatured states report that both proteins approximately double in hydrodynamic size upon denaturation, but that Klentaq expands somewhat more than Klenow. Proteins 2004;00:000–000. © 2004 Wiley‐Liss, Inc.
Reorganization in apo‐ and holo‐β‐lactoglobulin upon protonation of Glu89: Molecular dynamics and pKa calculations
Authors: Eberini Ivano , Baptista António M. , Gianazza Elisabetta , Fraternali Franca , Beringhelli Tiziana 
Published: February 2004

AbstractMolecular dynamics (MD) simulations starting from crystallographic data allowed us to directly account for the effects of the protonation state of Glu89 on the conformational stability of apo‐ and holo‐β‐lactoglobulin (BLG). In apo‐BLG simulations starting from the protonated crystal structure, we observe a long‐lived H‐bond interaction between the protonated Glu89 and Ser116. This interaction, sequestering the proton from the aqueous medium, explains a pKhalf value evaluated at pH 7.3 by continuum electrostatics/Monte Carlo computation on MD data, using linear response approximation. A very large root‐mean‐square deviation (RMSD; 5.11 Å) is observed for the EF loop between protonated and unprotonated apo‐BLG. This results from a quite different orientation of the EF loop that acts either as a closed or as an open lid above the protein calyx. Proton exchange by Glu89 in apo‐ but not in holo‐BLG is associated with a reorganization energy of 4.7 kcal/mol. A 3‐ns MD simulation starting from the crystal structure of protonated apo‐BLG, but considering the Glu89 as unprotonated, shows the progressive opening of the lid giving rise to the Tanford transition. In both holo‐BLG forms, the lid is most probably held in place by hydrophobic interactions of amino acid side‐chains of the EF loop with the palmitate hydrocarbon tail. Proteins 2004;00:000–000. © 2004 Wiley‐Liss, Inc.
Why does the Ras switch “break” by oncogenic mutations?
Authors: Shurki Avital , Warshel Arieh 
Published: February 2004

AbstractThe elucidation of the structure of the RasGAP complex provides what is perhaps the most detailed link between protein structure and cancer causing mutations. In particular, it is known that mutations of Gln 61 destroy the GTPase activity of the complex, locks the cell in its ON state and thus, can cause cancer. It is entirely unclear however, why this specific mutation is so important. The present work uncovers the elusive role of Gln 61 by computer simulation of the GTPase reaction in Ras, RasGAP and of their mutants. Simulations of the effects of mutations of Gln 61 reproduce the corresponding observed changes in activation energies and allow us to analyze the energy contributions to these effects. It is found that Gln 61 does not operate in a direct chemical way nor by a direct electrostatic or steric interaction with the transition state (TS). Instead, oncogenic mutations of Gln 61 lead to the destruction of the exquisitely preorganized catalytic configuration of the active site of the RasGAP complex. This “allosteric” effect causes a major reduction in the electrostatic stabilization of the TS. Our findings have general relevance to other proteins that control signal transduction processes. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Selection and affinity maturation of IgNAR variable domains targeting Plasmodium falciparum AMA1
Authors: Nuttall Stewart D. , Humberstone Karen S. , Krishnan Usha V. , Carmichael Jennifer A. , Doughty Larissa , Hattarki Meghan , Coley Andrew M. , Casey Joanne L. , Anders Robin F. , Foley Michael , Irving Robert A. , Hudson Peter J. 
Published: February 2004

AbstractThe new antigen receptor (IgNAR) is an antibody unique to sharks and consists of a disulphide‐bonded dimer of two protein chains, each containing a single variable and five constant domains. The individual variable (VNAR) domains bind antigen independently, and are candidates for the smallest antibody‐based immune recognition units. We have previously produced a library of VNAR domains with extensive variability in the CDR1 and CDR3 loops displayed on the surface of bacteriophage. Now, to test the efficacy of this library, and further explore the dynamics of VNAR antigen binding we have performed selection experiments against an infectious disease target, the malarial Apical Membrane Antigen‐1 (AMA1) from Plasmodium falciparum. Two related VNAR clones were selected, characterized by long (16‐ and 18‐residue) CDR3 loops. These recombinant VNARs could be harvested at yields approaching 5mg/L of monomeric protein from the E. coli periplasm, and bound AMA1 with nanomolar affinities (KD= ∼2 × 10−7 M). One clone, designated 12Y‐2, was affinity‐matured by error prone PCR, resulting in several variants with mutations mapping to the CDR1 and CDR3 loops. The best of these variants showed ∼10‐fold enhanced affinity over 12Y‐2 and was Plasmodium falciparum strain‐specific. Importantly, we demonstrated that this monovalent VNAR co‐localized with rabbit anti‐AMA1 antisera on the surface of malarial parasites and thus may have utility in diagnostic applications. Proteins 2004;00:000–000. © 2004 Wiley‐Liss, Inc.
Inter‐residue and solvent‐residue interactions in proteins: A statistical study on experimental structures
Authors: Chelli Riccardo , Gervasio Francesco Luigi , Procacci Piero , Schettino Vincenzo 
Published: February 2004

AbstractA large set of protein structures resolved by X‐ray or NMR techniques has been extracted from the Protein Data Bank and analyzed using statistical methods. In particular, we investigate the interactions between side chains and the interactions between solvent and side chains, pointing out on the possibility of including the solvent as part of a knowledge‐based potential. The solvent‐residue contacts are accounted for on the basis of the Voronoi's polyhedron analysis. Our investigation confirms the importance of hydrophobic residues in determining the protein stability. We observe that in general hydrophobic‐hydrophobic interactions and, more specifically, aromatic‐aromatic contacts tend to be increasingly distally separated in the primary sequence of proteins, thus connecting distinct secondary structure elements. A simple relation expressing the dependence of the protein free energy by the number of residues is proposed. Such a relation includes both the residue‐residue and the solvent‐residue contributions. The former is dominant for large size proteins, whereas for small sizes (number of residues less than 100) the two terms are comparable. Gapless threading experiments show that the solvent‐residue knowledge‐based potential yields a significant contribution with respect to discriminating the native structure of proteins. Such contribution is important especially for proteins of small size and is similar to that given by the most favorable residue‐residue knowledge‐based potential referring to hydrophobic‐hydrophobic interactions such as isoleucine‐leucine. In general, the inclusion of the solvent‐residue interaction produces a relevant increase of the free energy gap between the native structures and decoys. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Enzyme family classification by support vector machines
Authors: Cai C.Z. , Han L.Y. , Ji Z.L. , Chen Y.Z. 
Published: February 2004

AbstractOne approach for facilitating protein function prediction is to classify proteins into functional families. Recent studies on the classification of G‐protein coupled receptors and other proteins suggest that a statistical learning method, Support vector machines (SVM), may be potentially useful for protein classification into functional families. In this work, SVM is applied and tested on the classification of enzymes into functional families defined by the Enzyme Nomenclature Committee of IUBMB. SVM classification system for each family is trained from representative enzymes of that family and seed proteins of Pfam curated protein families. The classification accuracy for enzymes from 46 families and for non‐enzymes is in the range of 50.0% to 95.7% and 79.0% to 100% respectively. The corresponding Matthews correlation coefficient is in the range of 54.1% to 96.1%. Moreover, 80.3% of the 8,291 correctly classified enzymes are uniquely classified into a specific enzyme family by using a scoring function, indicating that SVM may have certain level of unique prediction capability. Testing results also suggest that SVM in some cases is capable of classification of distantly related enzymes and homologous enzymes of different functions. Effort is being made to use a more comprehensive set of enzymes as training sets and to incorporate multi‐class SVM classification systems to further enhance the unique prediction accuracy. Our results suggest the potential of SVM for enzyme family classification and for facilitating protein function prediction. Our software is accessible at http://jing.cz3.nus.edu.sg/cgi‐bin/svmprot.cgi. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Design Vulnerability Analysis and Design Improvement by Using Warranty Data
Authors: Yang Kai , Cekecek Ethem 
Published: February 2004

AbstractContinuous improvement in reliability is one of the key factors to success in the world automobile market. Good reliability can only be achieved through good design and manufacturing practice. Manufacturers want to allocate their limited resources to improvement in such a way that they can get the highest benefits. The warranty claims database contains more information than any other test for the reliability of products in actual use. Assisted by a design vulnerability index derived from the axiomatic design principle, warranty data can be used to identify the areas of the product such that the improvement of these areas will maximize the gain in reliability improvement. In this paper, we provide a methodology of utilizing warranty data to prioritize design improvement efforts based on design vulnerability and the feedback from warranty data. The methodology is illustrated with an example case. Copyright © 2004 John Wiley & Sons, Ltd.