bluuebunny/crossref_metadata_2025_split huggingface dataset:
An evolutionary and structure‐based docking model for glucocerebrosidase–saposin C and glucocerebrosidase–substrate interactions—Relevance for Gaucher disease
Authors: Atrian Sílvia , López‐Viñas Eduardo , Gómez‐Puertas Paulino , Chabás Amparo , Vilageliu Lluïsa , Grinberg Daniel 
Published: September 2007

AbstractGaucher disease, the most prevalent lysosomal storage disorder, is principally caused by malfunction of the lysosomal enzyme glucocerebrosidase (GBA), a 497‐amino acid membrane glycoprotein that catalyzes the hydrolysis of glucosylceramide to ceramide and glucose in the presence of an essential 84‐residue activator peptide named saposin C (SapC). Knowledge of the GBA structure, a typical (β/α)8 TIM barrel, explains the effect of few mutations, directly affecting or located near the catalytic site. To identify new regions crucial for proper GBA functionality, we analyzed the interactions of the enzyme with a second (substrate) and a third (cofactor) partner. We build 3D docking models of the GBA–SapC and the GBA–ceramide interactions, by means of methodologies that integrate both evolutive and structural information. The GBA–SapC docking model confirm the implication of three spatially closed regions of the GBA surface (TIM barrel‐helix 6 and helix 7, and the Ig‐like domain) in binding the SapC molecule. This model provides new basis to understand the pathogenicity of several mutations, such as the prevalent Leu444Pro, and the additive effect of Glu326Lys in the double mutant Glu326Lys‐Leu444Pro. Overall, 39 positions in which amino acid changes are known to cause Gaucher disease were localized in the GBA regions identified in this work. Our model is discussed in relation to the phenotype (pathogenic effect) of these mutations, as well as to the enzymatic activity of the recombinant proteins when available. Both data fully correlates with the proposed model, which will provide a new tool to better understand Gaucher disease and to design new therapy strategies. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Lipoprotein lipase: A bioinformatics criterion for assessment of mutations as a risk factor for cardiovascular disease
Authors: Glisic Sanja , Arrigo Patrizio , Alavantic Dragan , Perovic Vladimir , Prljic Jelena , Veljkovic Nevena 
Published: September 2007

AbstractLipoprotein lipase (LPL) is a key enzyme in lipid metabolism. Decrease of the LPL enzymatic activity leads to elevated triglycerides (TG) and reduced high‐density lipoprotein (HDL‐C levels), both risk factors for cardiovascular disease (CVD). Therefore, mutations, which decrease the LPL activity, may confer susceptibility to CVD. Here, the informational spectrum method (ISM), a virtual spectroscopy method for structure/function analysis of nucleotide and protein sequences, is applied for identification of evolutionary highly conserved information encoded by the primary structure of LPL. It was demonstrated that mutations, which alter the LPL enzymatic activity also alter this information. On the basis of this finding, an efficient and simple bioinformatics criterion for assessment of the pathogenic effect of LPL nonsynonymous single nucleotide substitution as a risk factor of CVD has been proposed. Proteins 2008. © 2007 Wiley‐Liss, Inc.
TPR domain of NrfG mediates complex formation between heme lyase and formate‐dependent nitrite reductase in Escherichia coli O157:H7
Authors: Han Dohyun , Kim Kyunggon , Oh Jongkil , Park Jungeun , Kim Youngsoo 
Published: September 2007

AbstractEscherichia coli synthesize C‐type cytochromes only during anaerobic growth in media supplemented with nitrate and nitrite. The reduction of nitrate to ammonium in the periplasm of Escherichia coli involves two separate periplasmic enzymes, nitrate reductase and nitrite reductase. The nitrite reductase involved, NrfA, contains cytochrome C and is synthesized coordinately with a membrane‐associated cytochrome C, NrfB, during growth in the presence of nitrite or in limiting nitrate concentrations. The genes NrfE, NrfF, and NrfG are required for the formate‐dependent nitrite reduction pathway, which involves at least two C‐type cytochrome proteins, NrfA and NrfB. The NrfE, NrfF, and NrfG genes (heme lyase complex) are involved in the maturation of a special C‐type cytochrome, apocytochrome C (apoNrfA), to cytochrome C (NrfA) by transferring a heme to the unusual heme binding motif of the Cys‐Trp‐Ser‐Cys‐Lys sequence in apoNrfA protein. Thus, in order to further investigate the roles of NrfG in the formation of heme lyase complex (NrfEFG) and in the interaction between heme lyase complex and formate‐dependent nitrite reductase (NrfA), we determined the crystal structure of NrfG at 2.05 Å. The structure of NrfG showed that the contact between heme lyase complex (NrfEFG) and NrfA is accomplished via a TPR domain in NrfG which serves as a binding site for the C‐terminal motif of NrfA. The portion of NrfA that binds to TPR domain of NrfG has a unique secondary motif, a helix followed by about a six‐residue C‐terminal loop (the so called “hook conformation”). This study allows us to better understand the mechanism of special C‐type cytochrome assembly during the maturation of formate‐dependent nitrite reductase, and also adds a new TPR binding conformation to the list of TPR‐mediated protein–protein interactions. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Computational studies of the structure, dynamics and native content of amyloid‐like fibrils of ribonuclease A
Authors: Colombo Giorgio , Meli Massimiliano , De Simone Alfonso 
Published: September 2007

AbstractThe characterization at atomic resolution of amyloid‐like protein aggregates is one of the fundamental problems of modern biology. In particular, the question whether native‐like domains are retained or completely refolded in the amyloid state and the identification of possible mechanisms for macromolecular ordered aggregation represent major unresolved puzzles. To address these issues, in this article we examine the stability, dynamics, and conservation of native‐like properties of several models of a previously designed amyloid‐like fibril of RNase A (Sambashivan et al., Nature 2005; 437:266–269). Through the use of molecular dynamics (MD) simulations, we have provided molecular‐level insights into the role of different parts of the sequence on the stability of fibrils, the collective properties of supramolecular complexes, and the presence of native‐like conformations and dynamics in supramolecular aggregates. We have been able to show that within the fibrils the three‐dimensional globular domain‐swapped units preserve the conformational, dynamical, and hydration properties typical of the monomeric state, providing a rationalization for the experimentally observed catalytic activity of fibrils. The nativeness of the globular domains is not affected by the amyloidogenic stretches, which determine the molecular recognition process underlying aggregation through the formation of a stable steric zipper motif. Moreover, through the study of the hydration features of a single sheet model, we have been able to show that polyglutamine stretches of the domain‐swapped ribonuclease tend to minimize the interaction with water in favor of sidechain–sidechain interactions, shedding light on the factors leading to the supramolecular assembly of β‐sheet layers into dry steric zippers. Proteins 2008. © 2007 Wiley‐Liss, Inc.
DOCKGROUND system of databases for protein recognition studies: Unbound structures for docking
Authors: Gao Ying , Douguet Dominique , Tovchigrechko Andrey , Vakser Ilya A. 
Published: September 2007

AbstractComputational docking approaches are important as a source of protein–protein complexes structures and as a means to understand the principles of protein association. A key element in designing better docking approaches, including search procedures, potentials, and scoring functions is their validation on experimentally determined structures. Thus, the databases of such structures (benchmark sets) are important. The previous, first release of the DOCKGROUND resource (Douguet et al., Bioinformatics 2006; 22:2612–2618) implemented a comprehensive database of cocrystallized (bound) protein–protein complexes in a relational database of annotated structures. The current release adds important features to the set of bound structures, such as regularly updated downloadable datasets: automatically generated nonredundant set, built according to most common criteria, and a manually curated set that includes only biological nonobligate complexes along with a number of additional useful characteristics. The main focus of the current release is unbound (experimental and simulated) protein–protein complexes. Complexes from the bound dataset are used to identify crystallized unbound analogs. If such analogs do not exist, the unbound structures are simulated by rotamer library optimization. Thus, the database contains comprehensive sets of complexes suitable for large scale benchmarking of docking algorithms. Advanced methodologies for simulating unbound conformations are being explored for the next release. The future releases will include datasets of modeled protein–protein complexes, and systematic sets of docking decoys obtained by different docking algorithms. The growing DOCKGROUND resource is designed to become a comprehensive public environment for developing and validating new docking methodologies. Proteins 2007. © 2007 Wiley‐Liss, Inc.
Acidic groups docked to well defined wetted pockets at the core of the binding interface: A tale of scoring and missing protein interactions in CAPRI
Authors: Bueno Marta , Camacho Carlos J. 
Published: September 2007

AbstractSome challenging targets in CAPRI (T24/25 and T26) involve binding solvent accessible acidic residues at the core of the binding interface, where they are always found immersed in crystal waters. In fact, Asp and Glu residues are more likely to form part of the hydrogen bond network of their surrounding crystal water molecules than to form a buried salt bridge. Interestingly, many of the crystal waters mediating the intermolecular interactions of the acidic groups are already present in the unbound structure, reinforcing the notion that some water molecules behave as an extension of the protein structure. This is in contrast to acidic groups found in the periphery of the binding interface that form ubiquitous salt bridges that cement the high affinity complex, while at the same time they are exposed to rapidly exchanging water molecules. Because of this, dichotomy implicit solvent scoring functions fail to properly rank these complexes by prioritizing salt bridges rather than water mediated contacts. A detailed analysis of Target 24, for which our group predicted two out of the four successful homology model complex structures, and Target26 reveal how crystal waters shape the binding cavities of acidic groups prior to binding, in agreement with the theory of anchor residues as mediators of protein recognition. Proteins 2007. © 2007 Wiley‐Liss, Inc.
HADDOCK versus HADDOCK: New features and performance of HADDOCK2.0 on the CAPRI targets
Authors: de Vries Sjoerd J. , van Dijk Aalt D. J. , Krzeminski Mickaël , van Dijk Mark , Thureau Aurelien , Hsu Victor , Wassenaar Tsjerk , Bonvin Alexandre M. J. J. 
Published: September 2007

AbstractHere we present version 2.0 of HADDOCK, which incorporates considerable improvements and new features. HADDOCK is now able to model not only protein–protein complexes but also other kinds of biomolecular complexes and multi‐component (N > 2) systems. In the absence of any experimental and/or predicted information to drive the docking, HADDOCK now offers two additional ab initio docking modes based on either random patch definition or center‐of‐mass restraints. The docking protocol has been considerably improved, supporting among other solvated docking, automatic definition of semi‐flexible regions, and inclusion of a desolvation energy term in the scoring scheme. The performance of HADDOCK2.0 is evaluated on the targets of rounds 4‐11, run in a semi‐automated mode using the original information we used in our CAPRI submissions. This enables a direct assessment of the progress made since the previous versions. Although HADDOCK performed very well in CAPRI (65% and 71% success rates, overall and for unbound targets only, respectively), a substantial improvement was achieved with HADDOCK2.0. Proteins 2007. © 2007 Wiley‐Liss, Inc.
SOFTDOCK application to protein–protein interaction benchmark and CAPRI
Authors: Li Nan , Sun Zhonghua , Jiang Fan 
Published: September 2007

AbstractThe success of molecular docking requires cooperation of sampling and scoring of various conformations. The SOFTDOCK package uses a coarse‐grained docking method to sample all possible conformations of complexes. SOFTDOCK uses a new Voronoi molecular surface and calculates several grid‐based scores. It is shown by the leave‐one‐out test that three geometry scores and an FTDOCK‐like electrostatics score contribute the most to the discrimination of near‐native conformations. However, an atom‐based solvation score is shown to be ineffective. It is also found that an increased Voronoi surface thickness greatly increases the accuracy of docking results. Finally, the clustering procedure is shown to improve the overall ranking, but leads to less accurate docking results. The application of SOFTDOCK in Critical Assessment of PRedicted Interactions involves four steps: (i) sampling with INTELEF; (ii) clustering; (iii) AMBER energy minimization; and (iv) manual inspection. Biological information from literature is used as filters in some of the sampling and manual inspection according to different targets. Two of our submissions have L_rmsd around 10 Å. Although they are not classified as acceptable solutions, they are considered successful because they are comparable to the accuracy of our method. Availability: SOFTDOCK is open source code and can be downloaded at http://bio.iphy.ac.cn Proteins 2007. © 2007 Wiley‐Liss, Inc.
Protein–protein docking: Progress in CAPRI rounds 6–12 using a combination of methods: The introduction of steered solvated molecular dynamics
Authors: Heifetz Alexander , Pal Sandeep , Smith Graham R. 
Published: September 2007

AbstractIn recent rounds of CAPRI, the Bii group has employed a combination of techniques for the prediction of the structure of protein–protein complexes. We currently use third‐party software for rigid‐body and semiflexible docking (MolFit, 3D‐Dock, RosettaDock), and our own steered molecular dynamics (SMD) technique for flexible refinement. SMD has also been found to be useful for discriminating near‐native from false positive docking decoys. In addition to this, a variety of sources of information, including multiple descriptors of interface quality combined with a QSAR‐like technique, published biological information, and continuum electrostatics calculations, are also used in the assessment of candidate complexes. We shall concentrate on results for CAPRI rounds 9–11 (targets 24–27). In these rounds, the Bii group has been successful in submitting a medium quality model for each of CAPRI targets 25 and 26, and a model of acceptable quality for target 27. Proteins 2007. © 2007 Wiley‐Liss, Inc.
Protein–protein docking in CAPRI using ATTRACT to account for global and local flexibility
Authors: May Andreas , Zacharias Martin 
Published: September 2007

AbstractA reduced protein model combined with a systematic docking approach has been employed to predict protein–protein complex structures in CAPRI rounds 6–11. The docking approach termed ATTRACT is based on energy minimization in translational and rotational degrees of freedom of one protein with respect to the second protein starting from many thousand initial protein partner placements. It also allows for approximate inclusion of global flexibility of protein partners during systematic docking by conformational relaxation of the partner proteins in precalculated soft collective backbone degrees of freedom. We have submitted models for six targets, achieved acceptable docking solutions for two targets, and predicted >20% correct contacts for five targets. Possible improvements of the docking approach in particular at the scoring and refinement steps are discussed. Proteins 2007. © 2007 Wiley‐Liss, Inc.
Assessing the energy landscape of CAPRI targets by FunHunt
Authors: London Nir , Schueler‐Furman Ora 
Published: September 2007

AbstractRosettaDock has repeatedly created high‐resolution structures of protein complexes in the CAPRI experiment, thanks to the explicit modeling of conformational changes of the monomers at the side chain level. These models can be selected based on their energy. During the search for the lowest‐energy model, RosettaDock samples a deep funnel around the native orientation, but additional funnels may appear in the energy landscape, especially in cases where backbone conformational changes occur upon binding. We have previously developed FunHunt, a Support Vector Machine‐based classifier that distinguishes the energy funnels around the native orientation from other funnels in the energy landscape. Here we assess the ability of FunHunt to help in model selection in the CAPRI experiment. For all of 12 recent CAPRI targets, FunHunt clearly identifies a near‐native funnel in comparison to the funnel around the lowest energy model identified by the RosettaDock global search protocol. FunHunt is also able to choose a near‐native orientation among models submitted by predictor groups, demonstrating its general applicability for model selection. This suggests that FunHunt will be a valuable tool in coming CAPRI rounds for the selection of models, and for the definition of regions that need further refinement with restricted backbone flexibility. Proteins 2007. © 2007 Wiley‐Liss, Inc.
A filter enhanced sampling and combinatorial scoring study for protein docking in CAPRI
Authors: Gong Xin Qi , Chang Shan , Zhang Qing Hua , Li Chun Hua , Shen Long Zhu , Ma Xiao Hui , Wang Ming Hui , Liu Bin , He Hong Qiu , Chen Wei Zu , Wang Cun Xin 
Published: September 2007

AbstractProtein–protein docking is usually exploited with a two‐step strategy, i.e., conformational sampling and decoy scoring. In this work, a new filter enhanced sampling scheme was proposed and added into the RosettaDock algorithm to improve the conformational sampling efficiency. The filter term is based on the statistical result that backbone hydrogen bonds in the native protein structures are wrapped by more than nine hydrophobic groups to shield them from attacks of water molecules (Fernandez and Scheraga, Proc Natl Acad Sci USA 2003;100:113–118). A combinatorial scoring function, ComScore, specially designed for the other‐type protein–protein complexes was also adopted to select the near native docked modes. ComScore was composed of the atomic contact energy, van der Waals, and electrostatic interaction energies, and the weight of each item was fit through the multiple linear regression approach. To analyze our docking results, the filter enhanced sampling scheme was applied to targets T12, T20, and T21 after the CAPRI blind test, and improvements were obtained. The ligand least root mean square deviations (L_rmsds) were reduced and the hit numbers were increased. ComScore was used in the scoring test for CAPRI rounds 9–12 with good success in rounds 9 and 11. Proteins 2007. © 2007 Wiley‐Liss, Inc.
Synthesis and antitumor activity of peptide‐paclitaxel conjugates
Authors: Papas Serafim , Akoumianaki Tonia , Kalogiros Christos , Hadjiarapoglou Lazaros , Theodoropoulos Panayiotis A. , Tsikaris Vassilios 
Published: September 2007

AbstractPaclitaxel (Pac) is the most important anticancer drug used mainly in treatment of breast, lung, and ovarian cancer and is being investigated for use as a single agent for treatment of lung cancer, advanced head and neck cancers, and adenocarcinomas of the upper gastrointestinal tract. In this work, we present the synthesis of five 2′‐paclitaxel‐substituted analogs in which paclitaxel was covalently bound to peptides or as multiple copies to synthetic carriers. Ac‐Cys(CH2CO‐2′‐Pac)‐Arg‐Gly‐Asp‐Arg‐NH2, Folyl‐Cys(CH2CO‐2′‐Pac)‐Arg‐Gly‐Asp‐Ser‐NH2, Ac‐[Lys‐Aib‐Cys(CH2CO‐2′‐Pac)]2‐NH2, Ac‐[Lys‐Aib‐Cys(CH2CO‐2′‐Pac)]3‐NH2 and Ac‐[Lys‐Aib‐Cys(CH2CO‐2′‐Pac)]4‐NH2 were synthesized using 2′‐halogeno‐acetylated paclitaxel derivatives. Paclitaxel conjugates showed greater solubility in water than paclitaxel and inhibited the proliferation of human breast, prostate, and cervical cancer cell lines. Although all synthesized compounds had an antiproliferative activity, the Ac‐[Lys‐Aib‐Cys(CH2CO‐2′‐Pac)]4‐NH2 derivative showed improved biological activity in comparison with paclitaxel in cervical and prostate human cancer cells. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
Loop propensity of the sequence YKGQP from staphylococcal nuclease: implications for the folding of nuclease
Authors: Patel Sunita , Sasidhar Yellamraju U. 
Published: September 2007

AbstractRecently we performed molecular dynamics (MD) simulations on the folding of the hairpin peptide DTVKLMYKGQPMTFR from staphylococcal nuclease in explicit water. We found that the peptide folds into a hairpin conformation with native and nonnative hydrogen‐bonding patterns. In all the folding events observed in the folding of the hairpin peptide, loop formation involving the region YKGQP was an important event. In order to trace the origins of the loop propensity of the sequence YKGQP, we performed MD simulations on the sequence starting from extended, polyproline II and native type I' turn conformations for a total simulation length of 300 ns, using the GROMOS96 force field under constant volume and temperature (NVT) conditions. The free‐energy landscape of the peptide YKGQP shows minima corresponding to loop conformation with Tyr and Pro side‐chain association, turn and extended conformational forms, with modest free‐energy barriers separating the minima. To elucidate the role of Gly in facilitating loop formation, we also performed MD simulations of the mutated peptide YKAQP (Gly → Ala mutation) under similar conditions starting from polyproline II conformation for 100 ns. Two minima corresponding to bend/turn and extended conformations were observed in the free‐energy landscape for the peptide YKAQP. The free‐energy barrier between the minima in the free‐energy landscape of the peptide YKAQP was also modest. Loop conformation is largely sampled by the YKGQP peptide, while extended conformation is largely sampled by the YKAQP peptide. We also explain why the YKGQP sequence samples type II turn conformation in these simulations, whereas the sequence as part of the hairpin peptide DTVKLMYKGQPMTFR samples type I' turn conformation both in the X‐ray crystal structure and in our earlier simulations on the folding of the hairpin peptide. We discuss the implications of our results to the folding of the staphylococcal nuclease. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
A general goodness‐of‐fit test for Markov and hidden Markov models
Authors: Titman Andrew C. , Sharples Linda D. 
Published: September 2007

AbstractMarkov models are a convenient and useful method of estimating transition rates between levels of a categorical response variable, such as a disease stage, which changes over time. In medical applications the response variable is typically observed at irregular intervals. A Pearson‐type goodness‐of‐fit test for such models was proposed by Aguirre‐Hernandez and Farewell (Statist. Med. 2002; 21:1899–1911), but this test is not applicable in the common situation where the process includes an absorbing state, such as death, for which the time of entry is known precisely nor when the data include censored state observations. This paper presents a modification to the Pearson‐type test to allow for these cases. An extension of the method, to allow for the class of hidden Markov models where the response variable is subject to misclassification error, is given. The method is applied to data on cardiac allograft vasculopathy in post‐heart‐transplant patients. Copyright © 2007 John Wiley & Sons, Ltd.