Pixel: a content management platform for quantitative omics data.

BACKGROUND: In biology, high-throughput experimental technologies, also referred as "omics" technologies, are increasingly used in research laboratories. Several thousands of gene expression measurements can be obtained in a single experiment. Researchers are routinely facing the challenge to annotate, store, explore and mine all the biological information they have at their disposal. We present here the Pixel web application (Pixel Web App), an original content management platform to help people involved in a multi-omics biological project. METHODS: The Pixel Web App is built with open source technologies and hosted on the collaborative development platform GitHub (https://github.com/Candihub/pixel). It is written in Python using the Django framework and stores all the data in a PostgreSQL database. It is developed in the open and licensed under the BSD 3-clause license. The Pixel Web App is also heavily tested with both unit and functional tests, a strong code coverage and continuous integration provided by CircleCI. To ease the development and the deployment of the Pixel Web App, Docker and Docker Compose are used to bundle the application as well as its dependencies. RESULTS: The Pixel Web App offers researchers an intuitive way to annotate, store, explore and mine their multi-omics results. It can be installed on a personal computer or on a server to fit the needs of many users. In addition, anyone can enhance the application to better suit their needs, either by contributing directly on GitHub (encouraged) or by extending Pixel on their own. The Pixel Web App does not provide any computational programs to analyze the data. Still, it helps to rapidly explore and mine existing results and holds a strategic position in the management of research data.

Improved PEP-FOLD Approach for Peptide and Miniprotein Structure Prediction.

Peptides and mini proteins have many biological and biomedical implications, which motivates the development of accurate methods, suitable for large-scale experiments, to predict their experimental or native conformations solely from sequences. In this study, we report PEP-FOLD2, an improved coarse grained approach for peptide de novo structure prediction and compare it with PEP-FOLD1 and the state-of-the-art Rosetta program. Using a benchmark of 56 structurally diverse peptides with 25-52 amino acids and a total of 600 simulations for each system, PEP-FOLD2 generates higher quality models than PEP-FOLD1, and PEP-FOLD2 and Rosetta generate near-native or native models for 95% and 88% of the targets, respectively. In the situation where we do not have any experimental structures at hand, PEP-FOLD2 and Rosetta return a near-native or native conformation among the top five best scored models for 80% and 75% of the targets, respectively. While the PEP-FOLD2 prediction rate is better than the ROSETTA prediction rate by 5%, this improvement is non-negligible because PEP-FOLD2 explores a larger conformational space than ROSETTA and consists of a single coarse-grained phase. Our results indicate that if the coarse-grained PEP-FOLD2 method is approaching maturity, we are not at the end of the game of mini-protein structure prediction, but this opens new perspectives for large-scale in silico experiments.

Isotype modulates epitope specificity, affinity, and antiviral activities of anti-HIV-1 human broadly neutralizing 2F5 antibody.

The constant heavy chain (CH1) domain affects antibody affinity and fine specificity, challenging the paradigm that only variable regions contribute to antigen binding. To investigate the role of the CH1 domain, we constructed IgA2 from the broadly neutralizing anti-HIV-1 2F5 IgG1, and compared 2F5 IgA2 and IgG binding affinity and functional activities. We found that 2F5 IgA2 bound to the gp41 membrane proximal external region with higher affinity than IgG1. Functionally, compared with IgG1, 2F5 IgA2 more efficiently blocked HIV-1 transcytosis across epithelial cells and CD4(+) cell infection by R5 HIV-1. The 2F5 IgG1 and IgA2 acted synergistically to fully block HIV-1 transfer from Langerhans to autologous CD4(+) T cells and to inhibit CD4(+) T-cell infection. Epitope mapping performed by screening a random peptide library and in silico docking modeling suggested that along with the 2F5 IgG canonical ELDKWA epitope on gp41, the IgG1 recognized an additional 3D-conformational epitope on the gp41 C-helix. In contrast, the IgA2 epitope included a unique conformational motif on the gp41 N-helix. Overall, the CH1 region of 2F5 contributes to shape its epitope specificity, antibody affinity, and functional activities. In the context of sexually transmitted infections such as HIV-1/AIDS, raising a mucosal IgA-based vaccine response should complement an IgG-based vaccine response in blocking HIV-1 transmission.

PEP-FOLD: an updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides.

In the context of the renewed interest of peptides as therapeutics, it is important to have an on-line resource for 3D structure prediction of peptides with well-defined structures in aqueous solution. We present an updated version of PEP-FOLD allowing the treatment of both linear and disulphide bonded cyclic peptides with 9-36 amino acids. The server makes possible to define disulphide bonds and any residue-residue proximity under the guidance of the biologists. Using a benchmark of 34 cyclic peptides with one, two and three disulphide bonds, the best PEP-FOLD models deviate by an average RMS of 2.75 Å from the full NMR structures. Using a benchmark of 37 linear peptides, PEP-FOLD locates lowest-energy conformations deviating by 3 Å RMS from the NMR rigid cores. The evolution of PEP-FOLD comes as a new on-line service to supersede the previous server. The server is available at: http://bioserv.rpbs.univ-paris-diderot.fr/PEP-FOLD.

The FAF-Drugs2 server: a multistep engine to prepare electronic chemical compound collections.

SUMMARY: The FAF-Drugs2 server is a web application that prepares chemical compound libraries prior to virtual screening or that assists hit selection/lead optimization before chemical synthesis or ordering. The FAF-Drugs2 web server is an enhanced version of the FAF-Drugs2 package that now includes Pan Assay Interference Compounds detection. This online toolkit has been designed through a user-centered approach with emphasis on user-friendliness. This is a unique online tool allowing to prepare large compound libraries with in house or user-defined filtering parameters. AVAILABILITY: The FAF-Drugs2 server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/FAF-Drugs/.

SA-Mot: a web server for the identification of motifs of interest extracted from protein loops.

The detection of functional motifs is an important step for the determination of protein functions. We present here a new web server SA-Mot (Structural Alphabet Motif) for the extraction and location of structural motifs of interest from protein loops. Contrary to other methods, SA-Mot does not focus only on functional motifs, but it extracts recurrent and conserved structural motifs involved in structural redundancy of loops. SA-Mot uses the structural word notion to extract all structural motifs from uni-dimensional sequences corresponding to loop structures. Then, SA-Mot provides a description of these structural motifs using statistics computed in the loop data set and in SCOP superfamily, sequence and structural parameters. SA-Mot results correspond to an interactive table listing all structural motifs extracted from a target structure and their associated descriptors. Using this information, the users can easily locate loop regions that are important for the protein folding and function. The SA-Mot web server is available at http://sa-mot.mti.univ-paris-diderot.fr.

fpocket: online tools for protein ensemble pocket detection and tracking.

Computational small-molecule binding site detection has several important applications in the biomedical field. Notable interests are the identification of cavities for structure-based drug discovery or functional annotation of structures. fpocket is a small-molecule pocket detection program, relying on the geometric alpha-sphere theory. The fpocket web server allows: (i) candidate pocket detection--fpocket; (ii) pocket tracking during molecular dynamics, in order to provide insights into pocket dynamics--mdpocket; and (iii) a transposition of mdpocket to the combined analysis of homologous structures--hpocket. These complementary online tools allow to tackle various questions related to the identification and annotation of functional and allosteric sites, transient pockets and pocket preservation within evolution of structural families. The server and documentation are freely available at http://bioserv.rpbs.univ-paris-diderot.fr/fpocket.

A fast method for large-scale de novo peptide and miniprotein structure prediction.

Although peptides have many biological and biomedical implications, an accurate method predicting their equilibrium structural ensembles from amino acid sequences and suitable for large-scale experiments is still missing. We introduce a new approach-PEP-FOLD-to the de novo prediction of peptides and miniproteins. It first predicts, in the terms of a Hidden Markov Model-derived structural alphabet, a limited number of local conformations at each position of the structure. It then performs their assembly using a greedy procedure driven by a coarse-grained energy score. On a benchmark of 52 peptides with 9-23 amino acids, PEP-FOLD generates lowest-energy conformations within 2.8 and 2.3 A Calpha root-mean-square deviation from the full nuclear magnetic resonance structures (NMR) and the NMR rigid cores, respectively, outperforming previous approaches. For 13 miniproteins with 27-49 amino acids, PEP-FOLD reaches an accuracy of 3.6 and 4.6 A Calpha root-mean-square deviation for the most-native and lowest-energy conformations, using the nonflexible regions identified by NMR. PEP-FOLD simulations are fast-a few minutes only-opening therefore, the door to in silico large-scale rational design of new bioactive peptides and miniproteins.

Mobyle: a new full web bioinformatics framework.

MOTIVATION: For the biologist, running bioinformatics analyses involves a time-consuming management of data and tools. Users need support to organize their work, retrieve parameters and reproduce their analyses. They also need to be able to combine their analytic tools using a safe data flow software mechanism. Finally, given that scientific tools can be difficult to install, it is particularly helpful for biologists to be able to use these tools through a web user interface. However, providing a web interface for a set of tools raises the problem that a single web portal cannot offer all the existing and possible services: it is the user, again, who has to cope with data copy among a number of different services. A framework enabling portal administrators to build a network of cooperating services would therefore clearly be beneficial. RESULTS: We have designed a system, Mobyle, to provide a flexible and usable Web environment for defining and running bioinformatics analyses. It embeds simple yet powerful data management features that allow the user to reproduce analyses and to combine tools using a hierarchical typing system. Mobyle offers invocation of services distributed over remote Mobyle servers, thus enabling a federated network of curated bioinformatics portals without the user having to learn complex concepts or to install sophisticated software. While being focused on the end user, the Mobyle system also addresses the need, for the bioinfomatician, to automate remote services execution: PlayMOBY is a companion tool that automates the publication of BioMOBY web services, using Mobyle program definitions. AVAILABILITY: The Mobyle system is distributed under the terms of the GNU GPLv2 on the project web site (http://bioweb2.pasteur.fr/projects/mobyle/). It is already deployed on three servers: http://mobyle.pasteur.fr, http://mobyle.rpbs.univ-paris-diderot.fr and http://lipm-bioinfo.toulouse.inra.fr/Mobyle. The PlayMOBY companion is distributed under the terms of the CeCILL license, and is available at http://lipm-bioinfo.toulouse.inra.fr/biomoby/PlayMOBY/.

PEP-FOLD: an online resource for de novo peptide structure prediction.

Rational peptide design and large-scale prediction of peptide structure from sequence remain a challenge for chemical biologists. We present PEP-FOLD, an online service, aimed at de novo modelling of 3D conformations for peptides between 9 and 25 amino acids in aqueous solution. Using a hidden Markov model-derived structural alphabet (SA) of 27 four-residue letters, PEP-FOLD first predicts the SA letter profiles from the amino acid sequence and then assembles the predicted fragments by a greedy procedure driven by a modified version of the OPEP coarse-grained force field. Starting from an amino acid sequence, PEP-FOLD performs series of 50 simulations and returns the most representative conformations identified in terms of energy and population. Using a benchmark of 25 peptides with 9-23 amino acids, and considering the reproducibility of the runs, we find that, on average, PEP-FOLD locates lowest energy conformations differing by 2.6 A Calpha root mean square deviation from the full NMR structures. PEP-FOLD can be accessed at http://bioserv.rpbs.univ-paris-diderot.fr/PEP-FOLD.

A coarse-grained protein force field for folding and structure prediction.

We have revisited the protein coarse-grained optimized potential for efficient structure prediction (OPEP). The training and validation sets consist of 13 and 16 protein targets. Because optimization depends on details of how the ensemble of decoys is sampled, trial conformations are generated by molecular dynamics, threading, greedy, and Monte Carlo simulations, or taken from publicly available databases. The OPEP parameters are varied by a genetic algorithm using a scoring function which requires that the native structure has the lowest energy, and the native-like structures have energy higher than the native structure but lower than the remote conformations. Overall, we find that OPEP correctly identifies 24 native or native-like states for 29 targets and has very similar capability to the all-atom discrete optimized protein energy model (DOPE), found recently to outperform five currently used energy models.

SABBAC: online Structural Alphabet-based protein BackBone reconstruction from Alpha-Carbon trace.

SABBAC is an on-line service devoted to protein backbone reconstruction from alpha-carbon trace. It is based on the assembly of fragments taken from a library of reduced size, selected from the encoding of the protein trace in a hidden Markov model-derived structural alphabet. The assembly of the fragments is achieved by a greedy algorithm, using an energy-based scoring. Alpha-carbon coordinates remain unaffected. SABBAC simply positions the missing backbone atoms, no further refinement is performed. From our tests, SABBAC performs equal or better than other similar on-line approach and is robust to deviations on the alpha-carbon coordinates. It can be accessed at http://bioserv.rpbs.jussieu.fr/SABBAC.html.