protein structure prediction Dotaz Zobrazit nápovědu
Proteins are naturally formed by domains edging their functional and structural properties. A domain out of the context of an entire protein can retain its structure and to some extent also function on its own. These properties rationalize construction of artificial fusion multidomain proteins with unique combination of various functions. Information on the specific functional and structural characteristics of individual domains in the context of new artificial fusion proteins is inevitably encoded in sequential order of composing domains defining their mutual spatial positions. So the challenges in designing new proteins with new domain combinations lie dominantly in structure/function prediction and its context dependency. Despite the enormous body of publications on artificial fusion proteins, the task of their structure/function prediction is complex and nontrivial. The degree of spatial freedom facilitated by a linker between domains and their mutual orientation driven by noncovalent interactions is beyond a simple and straightforward methodology to predict their structure with reasonable accuracy. In the presented manuscript, we tested methodology using available modeling tools and computational methods. We show that the process and methodology of such prediction are not straightforward and must be done with care even when recently introduced AlphaFold II is used. We also addressed a question of benchmarking standards for prediction of multidomain protein structures-x-ray or Nuclear Magnetic Resonance experiments. On the study of six two-domain protein chimeras as well as their composing domains and their x-ray structures selected from PDB, we conclude that the major obstacle for justified prediction is inappropriate sampling of the conformational space by the explored methods. On the other hands, we can still address particular steps of the methodology and improve the process of chimera proteins prediction.
BACKGROUND: PsbO, the manganese-stabilising protein, is an indispensable extrinsic subunit of photosystem II. It plays a crucial role in the stabilisation of the water-splitting Mn4CaO5 cluster, which catalyses the oxidation of water to molecular oxygen by using light energy. PsbO was also demonstrated to have a weak GTPase activity that could be involved in regulation of D1 protein turnover. Our analysis of psbO sequences showed that many angiosperm species express two psbO paralogs, but the pairs of isoforms in one species were not orthologous to pairs of isoforms in distant species. RESULTS: Phylogenetic analysis of 91 psbO sequences from 49 land plant species revealed that psbO duplication occurred many times independently, generally at the roots of modern angiosperm families. In spite of this, the level of isoform divergence was similar in different species. Moreover, mapping of the differences on the protein tertiary structure showed that the isoforms in individual species differ from each other on similar positions, mostly on the luminally exposed end of the β-barrel structure. Comparison of these differences with the location of differences between PsbOs from diverse angiosperm families indicated various selection pressures in PsbO evolution and potential interaction surfaces on the PsbO structure. CONCLUSIONS: The analyses suggest that similar subfunctionalisation of PsbO isoforms occurred parallelly in various lineages. We speculate that the presence of two PsbO isoforms helps the plants to finely adjust the photosynthetic apparatus in response to variable conditions. This might be mediated by diverse GTPase activity, since the isoform differences predominate near the predicted GTP-binding site.
- MeSH
- aminokyseliny metabolismus MeSH
- druhová specificita MeSH
- fotosystém II (proteinový komplex) chemie metabolismus MeSH
- fylogeneze * MeSH
- Magnoliopsida genetika metabolismus MeSH
- molekulární modely MeSH
- otevřené čtecí rámce genetika MeSH
- protein - isoformy chemie metabolismus MeSH
- rostlinné geny MeSH
- sekundární struktura proteinů MeSH
- sekvence aminokyselin MeSH
- substituce aminokyselin MeSH
- terciární struktura proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Here we introduce the Protein Cutter (http:// biochemie.upol.cz/software/proteincutter), a web application for the prediction of results of protein digestion by proteolytic enzymes, which is accessible over the Internet network. In the beginning, previous and current approaches for protein sequencing are summarized. This includes the use of dinitrofluorobenzene and substituted isothiocyanate reagents as well as mass-spectrometry-based strategies and translation of genomic sequences. The following text characterizes bioinformatics as a modern scientific discipline, which solves problems arising from the management and analysis of biological data. The most important nucleotide and amino acid sequence databases are described together with the databases of DNA and protein structures. The program Protein Cutter, which is described in detail with respect to its design and technology, allows predicting peptide sequences generated by proteolytic digestion of a protein (represented by a user-entered amino acid or coding nucleotide sequence). In addition to other comparable applications, Protein Cutter offers more complex information calculated from amino acid sequences (i.e. molecular mass, amino acid composition, isoelectric point, hydropathicity index etc.), it works with nucleotide sequences upon automatic translation, it is open and friendly for user-entered cutting rules and provides more options for the filtration and sorting of results.
- MeSH
- databáze proteinů * MeSH
- genomika MeSH
- hmotnostní spektrometrie * metody přístrojové vybavení využití MeSH
- matematické výpočty počítačové MeSH
- molekulární sekvence - údaje * MeSH
- peptidové mapování * MeSH
- polymerázová řetězová reakce metody využití MeSH
- proteasy * MeSH
- proteomika MeSH
- sekvence aminokyselin * MeSH
- sekvenční analýza proteinů * MeSH
- software * MeSH
- systémy řízení databází * MeSH
- výpočetní biologie MeSH
- Publikační typ
- práce podpořená grantem MeSH
SUMMARY: We present the cpPredictor webserver that implements a novel template-based method for prediction of secondary structure of RNA. The method outperforms available prediction methods as it uses RNA structures of related molecules, either predicted or experimentally identified, as structural templates. The server aims at three major tasks: i) prediction of RNA secondary structures that are difficult to predict by available methods, ii) characterization of uncharacterized RNAs as compatible or incompatible with a chosen template structure and iii) an identification of the most relevant structure among different candidate structures of a single RNA ambiguously predicted by available methods. The web server is accompanied with a comprehensive documentation. AVAILABILITY AND IMPLEMENTATION: The web server is freely available at http://cppredictor.elixir-czech.cz/. The source code of the cpPredictor algorithm is freely available from the webserver under the Apache License, Version 2.0.
To find an effective drug for Zika virus, it is important to understand how numerous proteins which are critical for the virus' structure and function interact with their counterparts. One approach to inhibiting the flavivirus is to deter its ability to bind onto glycoproteins; however, the crystal structures of envelope proteins of the ever-evolving viral strains that decipher glycosidic or drug-molecular interactions are not always available. To fill this gap, we are reporting a holistic, simulation-based approach to predict compounds that will inhibit ligand binding onto a structurally unresolved protein, in this case the Zika virus envelope protein (ZVEP), by developing a three-dimensional general structure and analyzing sites at which ligands and small drug-like molecules interact. By examining how glycan molecules and small-molecule probes interact with a freshly resolved ZVEP homology model, we report the susceptibility of ZVEP to inhibition via two small molecules, ZINC33683341 and ZINC49605556-by preferentially binding onto the primary receptor responsible for the virus' virulence. Antiviral activity was confirmed when ZINC33683341 was tested in cell culture. We anticipate the results to be a starting point for drug discovery targeting Zika virus and other emerging pathogens.
- MeSH
- antivirové látky chemie farmakologie MeSH
- Cercopithecus aethiops MeSH
- knihovny malých molekul chemie farmakologie MeSH
- molekulární modely MeSH
- počítačová simulace MeSH
- polysacharidy metabolismus MeSH
- proteiny virového obalu antagonisté a inhibitory chemie MeSH
- strukturní homologie proteinů MeSH
- vazebná místa MeSH
- Vero buňky MeSH
- virová nálož účinky léků MeSH
- virus zika účinky léků metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Crystallography provides unique information about the arrangement of water molecules near protein surfaces. Using a nonredundant set of 2818 protein crystal structures with a resolution of better than 1.8 Å, the extent and structure of the hydration shell of all 20 standard amino-acid residues were analyzed as function of the residue conformation, secondary structure and solvent accessibility. The results show how hydration depends on the amino-acid conformation and the environment in which it occurs. After conformational clustering of individual residues, the density distribution of water molecules was compiled and the preferred hydration sites were determined as maxima in the pseudo-electron-density representation of water distributions. Many hydration sites interact with both main-chain and side-chain amino-acid atoms, and several occurrences of hydration sites with less canonical contacts, such as carbon-donor hydrogen bonds, OH-π interactions and off-plane interactions with aromatic heteroatoms, are also reported. Information about the location and relative importance of the empirically determined preferred hydration sites in proteins has applications in improving the current methods of hydration-site prediction in molecular replacement, ab initio protein structure prediction and the set-up of molecular-dynamics simulations.
- MeSH
- aminokyseliny analýza MeSH
- databáze proteinů MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- proteiny chemie MeSH
- sekundární struktura proteinů MeSH
- voda analýza MeSH
- vodíková vazba MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cholesteryl ester transfer protein (CETP), an enzyme which catalyses the transfer of cholesteryl ester from HDL to VLDL, is a promising target for discovery of novel antihyperlipidemic agents due to its pivotal role in HDL metabolism and reverse cholesterol transport. Quantitative structure activity relationship study of a series of CETP inhibitors was carried out using genetic function approximation to study various structural requirements for CETP inhibition. Various lipophilic, electronic, geometric and spatial descriptors were correlated with CETP inhibitory activity. Developed models were found predictive as indicated by their good r2pred values and satisfactory internal and external cross-validation results. Study reveals that lipophilicity (ClogP), with parabolic relationship, contributed significantly to the activity along with some electronic, geometric and quantum mechanical descriptors. The present study can be applied to future lead optimization of CETP inhibitors.
BACKGROUND: Protein-protein interactions (PPI) play a key role in an investigation of various biochemical processes, and their identification is thus of great importance. Although computational prediction of which amino acids take part in a PPI has been an active field of research for some time, the quality of in-silico methods is still far from perfect. RESULTS: We have developed a novel prediction method called INSPiRE which benefits from a knowledge base built from data available in Protein Data Bank. All proteins involved in PPIs were converted into labeled graphs with nodes corresponding to amino acids and edges to pairs of neighboring amino acids. A structural neighborhood of each node was then encoded into a bit string and stored in the knowledge base. When predicting PPIs, INSPiRE labels amino acids of unknown proteins as interface or non-interface based on how often their structural neighborhood appears as interface or non-interface in the knowledge base. We evaluated INSPiRE's behavior with respect to different types and sizes of the structural neighborhood. Furthermore, we examined the suitability of several different features for labeling the nodes. Our evaluations showed that INSPiRE clearly outperforms existing methods with respect to Matthews correlation coefficient. CONCLUSION: In this paper we introduce a new knowledge-based method for identification of protein-protein interaction sites called INSPiRE. Its knowledge base utilizes structural patterns of known interaction sites in the Protein Data Bank which are then used for PPI prediction. Extensive experiments on several well-established datasets show that INSPiRE significantly surpasses existing PPI approaches.
