15 research outputs found
Conception de Ligands Protéiques par Bioinformatique et Modélisation Moléculaire
No full textThe increasing structural and functional knowledge of proteins gives us a clearer idea of how they interact. This information could be used to design new compounds, able to interact with a wide variety of interesting targets, as well as improve our comprehension of this phenomenon. This work presents the development of a new method enabling the design of protein ligands based on the transfer of a set of amino acids of a known ligand, contributing to the binding of a chosen target on a host protein, containing less than 100 residues (mini-proteins). These host proteins, able to reproduce the interaction after motif insertion, are identified in a systematic manner from the PDB. This approach has been applied to the development of new ligands of the Kv1.2 channel using the structural and functional knowledge of the interaction with the BgK toxin. Three ligands have been designed with inhibition constants in the micro molar range. Those results demonstrate the possibility of designing new ligands with a method based on the transfer of a functional motif of residues on a new scaffold which is sterically and electrostatically compatible with the interaction targeted.L'accroissement des connaissances, structurales et fonctionnelles, des protéines nous donne désormais une vision plus précise des phénomènes d'interaction. L'utilisation de ces informations pour le développement de ligands permettrait d'obtenir de nouveaux composés, capables d'interagir avec diverses cibles d'intérêt, et d'améliorer notre compréhension de ces interactions. Ce travail présente le développement d'une nouvelle méthode de conception de ligands protéiques, laquelle repose sur le transfert d'un groupe de résidus, appartenant à un ligand connu et contribuant de façon importante à la liaison avec une cible d'intérêt, sur une protéine hôte, de moins de 100 résidus (mini-protéines). L'identification de protéines hôtes, aptes à reproduire l'interaction après transfert du motif, est réalisée de manière systématique à partir des structures présentes dans la PDB. L'approche a été appliquée pour le développement de ligands du canal Kv1.2, à partir de connaissances structurales et fonctionnelles de l'interaction de ce même canal avec la toxine BgK. Trois ligands, possédant des constantes d'inhibition micro molaires, ont été ainsi conçus. Ces résultats démontrent la possibilité de mettre en application une méthode de conception de ligands, basée sur le transfert de motifs de « hotspots », sur une plateforme structurale de nature protéique, dont les aspects stérique et électrostatique sont compatibles avec une interaction donnée
Replication Data for "multistrap: boosting phylogenetic analyses with structural information"
No full textDataset for the replication of the analysis presented in "multistrap: boosting phylogenetic analyses with structural information".
Overview of the Content of the uploaded dataset and its Structure:
ids: Contains the full list of the identifiers of the datasets.
ids_titration: Contains the 56 identifiers used for the titration analysis.
pdb/: Contains all the PDB structures for each of the sequences of each dataset.
alignments/: Contains the untrimmed alignments produced with mTMalign, used for downstream analyses.
matrices/
{IMD,ME}/: Contains the distance matrices computed using the untrimmed mTMalign alignments.
/replicates: Contains 100 replicate distance matrices for each dataset for IMD.
trees/
{IMD,ME,ML}/: Trees computed with the tree method specified in the folder name.
/replicates: Contains the 100 replicate trees for each dataset.
auc_analysis/: Contains the files necessary to replicate the AUC analysis
: un outil efficace pour l’amélioration de la stabilité numérique des calculs en analyse génomique
No full textLa reproduction des analyses bio-informatiques de routine est difficile en raison d’une combinaison de facteurs difficiles à contrôler. Nextflow est un gestionnaire de flux (workflow manager) qui utilise la technologie des conteneurs pour assurer un déploiement et une reproductibilité efficace des pipelines d’analyse computationnelle. Les pipelines tiers peuvent être portés dans Nextflow avec un recodage minimum. Nous montrons ici à l’aide d’exemples concrets comment la quantification des niveaux d’expression, l’annotation de génomes et la reconstruction de phylogénie peuvent se révéler non reproductibles lorsqu’elles sont réalisées sur des plates-formes UNIX différentes, alors qu’elles deviennent stables lorsqu’elles sont déployées dans Nextflow. Nextflow est disponible sur www.nextflow.i
Multiple sequence alignment computation using the T-Coffee regressive algorithm implementation
No full textMany fields of biology rely on the inference of accurate multiple sequence alignments (MSA) of biological sequences. Unfortunately, the problem of assembling an MSA is NP-complete thus limiting computation to approximate solutions using heuristics solutions. The progressive algorithm is one of the most popular frameworks for the computation of MSAs. It involves pre-clustering the sequences and aligning them starting with the most similar ones. The scalability of this framework is limited, especially with respect to accuracy. We present here an alternative approach named regressive algorithm. In this framework, sequences are first clustered and then aligned starting with the most distantly related ones. This approach has been shown to greatly improve accuracy during scale-up, especially on datasets featuring 10,000 sequences or more. Another benefit is the possibility to integrate third-party clustering methods and third-party MSA aligners. The regressive algorithm has been tested on up to 1.5 million sequences, its implementation is available in the T-Coffee package
Inferring phylogenetic trees from intramolecular distances with Phylo-IMD
No full textPhylogenetic reconstruction is one of the most widely used modelling techniques in biology. While most available methods involve the use of sequence-based comparison it has long been discussed whether structural information could be used to further inform tree reconstruction. In this study, we explored the usability of intra molecular distances as a potential evolutionary character. Using multiple sequence alignment to identify homologous internal distances, we have defined a pairwise comparison metric, IMD, that can be used in combination with any distance-based phylogenetic method and lends itself to the measure of branch support values using a procedure similar to the Felsenstein bootstrap. The IMD metric was validated on a dataset of 508 protein families featuring a total of 10,668 protein sequences with known X-Ray structures. The benchmark was carried out using sequence-based maximum likelihood trees as references. Our most important finding is the observation that the IMD bootstrap support is a strong indicator of topological agreement between the structure-based IMD trees and their sequence-based maximum likelihood counterparts. We also developed a titration procedure that allowed us to determine that all things being equal, the evolutionary signal measured by IMD is roughly twice denser than the equivalent sequence-based signal. Altogether our results suggest the suitability of structure-based phylogeny for evolutionary analysis, but above all, they indicate structure-based phylogeny as a powerful means of providing new supporting evidence to protein phylogenetic tree reconstruction
PSI/TM-Coffee: a web server for fast and accurate multiple sequence alignments of regular and transmembrane proteins using homology extension on reduced databases
No full textThe PSI/TM-Coffee web server performs multiple sequence alignment (MSA) of proteins by combining homology extension with a consistency based alignment approach. Homology extension is performed with Position Specific Iterative (PSI) BLAST searches against a choice of redundant and non-redundant databases. The main novelty of this server is to allow databases of reduced complexity to rapidly perform homology extension. This server also gives the possibility to use transmembrane proteins (TMPs) reference databases to allow even faster homology extension on this important category of proteins. Aside from an MSA, the server also outputs topological prediction of TMPs using the HMMTOP algorithm. Previous benchmarking of the method has shown this approach outperforms the most accurate alignment methods such as MSAProbs, Kalign, PROMALS, MAFFT, ProbCons and PRALINE™. The web server is available at http://tcoffee.crg.cat/tmcoffee.This work was supported by Plan Nacional [BFU2011-28575 to C.N., P.D.]; Center for Genomic Regulation (CRG); ‘Fundació Obra Social la Caixa’ (to E.W.F, M.C); Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017’ [SEV-2012–0208]; Center for Genomic Regulation (CRG)
PSI/TM-Coffee: a web server for fast and accurate multiple sequence alignments of regular and transmembrane proteins using homology extension on reduced databases
No full textThe PSI/TM-Coffee web server performs multiple sequence alignment (MSA) of proteins by combining homology extension with a consistency based alignment approach. Homology extension is performed with Position Specific Iterative (PSI) BLAST searches against a choice of redundant and non-redundant databases. The main novelty of this server is to allow databases of reduced complexity to rapidly perform homology extension. This server also gives the possibility to use transmembrane proteins (TMPs) reference databases to allow even faster homology extension on this important category of proteins. Aside from an MSA, the server also outputs topological prediction of TMPs using the HMMTOP algorithm. Previous benchmarking of the method has shown this approach outperforms the most accurate alignment methods such as MSAProbs, Kalign, PROMALS, MAFFT, ProbCons and PRALINE™. The web server is available at http://tcoffee.crg.cat/tmcoffee.This work was supported by Plan Nacional [BFU2011-28575 to C.N., P.D.]; Center for Genomic Regulation (CRG); ‘Fundació Obra Social la Caixa’ (to E.W.F, M.C); Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017’ [SEV-2012–0208]; Center for Genomic Regulation (CRG)
Naphthalene diimides (NDI) in highly stable pH-neutral aqueous organic redox flow batteries
No full textFunding Information: This work was supported by the Swedish Research Council (grant 2015-04853) and the Swedish Research Council FORMAS (grant 942-2015-411). Publisher Copyright: © 2021 The Author(s)In the pursuit of environmentally friendly energy storage, aqueous organic redox flow batteries (AORFBs) that use naphthalene diimide hold promise for successful application. In the present article, two different naphthalene diimides (NDI) are studied as negative electrolyte materials for pH-neutral aqueous organic/organometallic redox flow batteries. The two molecules, one core-unsubstituted NDI (2H-NDI) and one core-dimethylamino substituted NDI (2DMA-NDI) are coupled with a solubilized ferrocene (BTMAP-Fc) at a concentration of 50 mM in phosphate buffered potassium chloride. High energy efficiencies and coulombic efficiencies were obtained for both batteries, but a gradual capacity fade was observed while cycling. However, when changing the cation of the supporting electrolyte from potassium to ammonium, similar energy and coulombic efficiencies were obtained, but with undetectable capacity losses over 320 cycles. Finally, 2H-NDI and BTMAP-Fc at 500 mM were tested in the ammonium-based electrolyte, and while obtaining high coulombic efficiency, the energy efficiency and cycling stability decreased compared to the same system at lower concentration. It is concluded that loss of activity is mainly due to formation of electrochemically inactive compounds and that the electrolyte cation is of great importance for the outcome. Important design strategies for AORFB molecules include using supporting salts that prevent self-association and introducing sterically hindering substituents to the structures.Peer reviewe
