Annuaire
2023
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Two decades of Martini: Better beads, broader scope
- Journal : WIREs Computational Molecular Science
- 2023
- Abstract The Martini model, a coarse-grained force field for molecular dynamics simulations, has been around for nearly two decades. Originally developed for lipid-based systems by the groups of Marrink and Tieleman, the Martini model has over the years been extended as a community effort to the current level of a general-purpose force field. Apart from the obvious benefit of a reduction in computational cost, the popularity of the model is largely due to the systematic yet intuitive building-block approach that underlies the model, as well as the open nature of the development and its continuous validation. The easy implementation in the widely used Gromacs software suite has also been instrumental. Since its conception in 2002, the Martini model underwent a gradual refinement of the bead interactions and a widening scope of applications. In this review, we look back at this development, culminating with the release of the Martini 3 version in 2021. The power of the model is illustrated with key examples of recent important findings in biological and material sciences enabled with Martini, as well as examples from areas where coarse-grained resolution is essential, namely high-throughput applications, systems with large complexity, and simulations approaching the scale of whole cells. This article is categorized under: Software > Molecular Modeling Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods Structure and Mechanism > Computational Materials Science Structure and Mechanism > Computational Biochemistry and Biophysics
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Automatic Optimization of Lipid Models in the Martini Force Field Using SwarmCG
- Journal : Journal of Chemical Information and Modeling
- 2023
- After two decades of continued development of the Martini coarse-grained force field (CG FF), further refinment of the already rather accurate Martini lipid models has become a demanding task that could benefit from integrative data-driven methods. Automatic approaches are increasingly used in the development of accurate molecular models, but they typically make use of specifically designed interaction potentials that transfer poorly to molecular systems or conditions different than those used for model calibration. As a proof of concept, here, we employ SwarmCG, an automatic multiobjective optimization approach facilitating the development of lipid force fields, to refine specifically the bonded interaction parameters in building blocks of lipid models within the framework of the general Martini CG FF. As targets of the optimization procedure, we employ both experimental observables (top-down references: area per lipid and bilayer thickness) and all-atom molecular dynamics simulations (bottom-up reference), which respectively inform on the supra-molecular structure of the lipid bilayer systems and on their submolecular dynamics. In our training sets, we simulate at different temperatures in the liquid and gel phases up to 11 homogeneous lamellar bilayers composed of phosphatidylcholine lipids spanning various tail lengths and degrees of (un)saturation. We explore different CG representations of the molecules and evaluate improvements a posteriori using additional simulation temperatures and a portion of the phase diagram of a DOPC/DPPC mixture. Successfully optimizing up to ∼80 model parameters within still limited computational budgets, we show that this protocol allows the obtainment of improved transferable Martini lipid models. In particular, the results of this study demonstrate how a fine-tuning of the representation and parameters of the models may improve their accuracy and how automatic approaches, such as SwarmCG, may be very useful to this end.
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Protocol to measure protein-RNA binding using double filter-binding assays followed by phosphorimaging or high-throughput sequencing
- Journal : STAR Protoc
- 2023
- Binding affinity quantitatively describes the strength of a molecular interaction and is reported by the equilibrium dissociation constant (KD). Here, we present a protocol to measure KD of mammalian microRNA-loaded Argonaute2 protein by double filter binding. We describe steps for radiolabeling target RNA, measuring concentration of binding-competent protein, setting up binding reactions, separating protein-bound RNA from protein-unbound RNA, preparing library for Illumina sequencing, and performing data analysis. Our protocol is easily applied to other RNA- or DNA-binding proteins. For complete details on the use and execution of this protocol, please refer to Jouravleva et al.
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Orientational Wetting and Topological Transitions in Confined Solutions of Semiflexible Polymers
- Journal : Macromolecules
- 2023
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4D epigenomics: deciphering the coupling between genome folding and epigenomic regulation with biophysical modeling.
- Journal : Curr Opin Genet Dev
- 2023
- Recent experimental observations suggest a strong coupling between the 3D nuclearchromosome organization and epigenomics. However, the mechanistic and functionalbases of such interplay remain elusive. In this review, we describe howbiophysical modeling has been instrumental in characterizing how genome foldingmay impact the formation of epigenomic domains and, conversely, how epigenomicmarks may affect chromosome conformation. Finally, we discuss how this mutualfeedback loop between chromatin organization and epigenome regulation, via theformation of physicochemical nanoreactors, may represent a key functional role of3D compartmentalization in the assembly and maintenance of stable - but yetplastic - epigenomic landscapes.
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Cortisol Interaction with Aquaporin-2 Modulates Its Water Permeability: Perspectives for Non-Genomic Effects of Corticosteroids
- Journal : Int J Mol Sci
- 2023
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Structural Studies of Pif1 Helicases from Thermophilic Bacteria
- Journal : Microorganisms
- 2023
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Nucleosome dyad determines the H1 C-terminus collapse on distinct DNA arms
- Journal : Structure
- 2023
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Nonstructural N- and C-tails of Dbp2 confer the protein full helicase activities
- Journal : J Biol Chem
- 2023
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One model fits all: Combining inference and simulation of gene regulatory networks
- Journal : PLoS Comput Biol
- 2023
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RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.
- Journal : Nat Commun
- 2023
- Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitrythat coordinates gene expression at multiple levels from chromatin to mRNAprocessing. Recently, ribosome biogenesis and translation have emerged as keypathways that efficiently control stem cell homeostasis, yet the underlyingmolecular mechanisms remain largely unknown. Here, we identified RSL24D1 ashighly expressed in both mouse and human pluripotent stem cells. RSL24D1 isassociated with nuclear pre-ribosomes and is required for the biogenesis of 60Ssubunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairsglobal translation, particularly of key pluripotency factors and of componentsfrom the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact ondifferentiation, RSL24D1 depletion significantly alters ESC self-renewal andlineage commitment choices. Altogether, these results demonstrate thatRSL24D1-dependant ribosome biogenesis is both required to sustain the expressionof pluripotent transcriptional programs and to silence PRC2-regulateddevelopmental programs, which concertedly dictate ESC homeostasis.
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Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2.
- Journal : Nat Commun
- 2023
- Type I and III interferons (IFN-I/λ) are important antiviral mediators againstSARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells(pDC) are the predominant IFN-I/λ source following their sensing ofSARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCsrequires sustained integrin-mediated cell adhesion with infected cells. In turn,pDCs restrict viral spread by an IFN-I/λ response directed towardSARS-CoV-2-infected cells. This specialized function enables pDCs to efficientlyturn-off viral replication, likely via a local response at the contact site withinfected cells. By exploring the pDC response in SARS-CoV-2 patients, we furtherdemonstrate that pDC responsiveness inversely correlates with the severity of thedisease. The pDC response is particularly impaired in severe COVID-19 patients.Overall, we propose that pDC activation is essential to controlSARS-CoV-2-infection. Failure to develop this response could be important tounderstand severe cases of COVID-19.
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Functional analysis of Wolbachia Cid effectors unravels cooperative interactions to target host chromatin during replication
- Journal : PLOS Pathogens
- 2023
- Wolbachia are common bacteria among terrestrial arthropods. These endosymbionts transmitted through the female germline manipulate their host reproduction through several mechanisms whose most prevalent form called Cytoplasmic Incompatibility -CI- is a conditional sterility syndrome eventually favoring the infected progeny. Upon fertilization, the sperm derived from an infected male is only compatible with an egg harboring a compatible Wolbachia strain, this sperm leading otherwise to embryonic death. The Wolbachia Cif factors CidA and CidB responsible for CI and its neutralization function as a Toxin-Antitoxin system in the mosquito host Culex pipiens . However, the mechanism of CidB toxicity and its neutralization by the CidA antitoxin remain unexplored. Using transfected insect cell lines to perform a structure-function analysis of these effectors, we show that both CidA and CidB are chromatin interactors and CidA anchors CidB to the chromatin in a cell-cycle dependent-manner. In absence of CidA, the CidB toxin localizes to its own chromatin microenvironment and acts by preventing S-phase completion, independently of its deubiquitylase -DUB- domain. Experiments with transgenic Drosophila show that CidB DUB domain is required together with CidA during spermatogenesis to stabilize the CidA-CidB complex. Our study defines CidB functional regions and paves the way to elucidate the mechanism of its toxicity.
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Facilitating CG Simulations with MAD: The MArtini Database Server
- Journal : Journal of Chemical Information and Modeling
- 2023
- The MArtini Database (MAD - https://mad.ibcp.fr) is a web server designed for the sharing of structures and topologies of molecules parametrized with the Martini coarse-grained (CG) force field. MAD can also convert atomistic structures into CG structures and prepare complex systems (including proteins, lipids, etc.) for molecular dynamics (MD) simulations at the CG level. It is dedicated to the generation of input files for Martini 3, the most recent version of this popular CG force field. Specifically, the MAD server currently includes tools to submit or retrieve CG models of a wide range of molecules (lipids, carbohydrates, nanoparticles, etc.), transform atomistic protein structures into CG structures and topologies, with fine control on the process and assemble biomolecules into large systems, and deliver all files necessary to start simulations in the GROMACS MD engine.
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Specific Xray diffraction patterns of membrane proteins caused by secondary structure collinearity.
- Journal : Biochim Biophys Acta Biomembr
- 2023
- Diffraction anisotropy is a phenomenon that impacts more specifically membraneproteins, compared to soluble ones, but the reasons for this discrepancy remainedunclear. Often, it is referred to a difference in resolution limits betweenhighest and lowest diffraction limits as a signature for anisotropy. We show inthis article that there is no single correlation between anisotropy anddifference in resolution limits, with notably a substantial number of structuresdisplaying various anisotropy with no difference in resolution limits. We furtherinvestigated diffraction intensity profiles, and observed a peak centred on 4.9 Åresolution more predominant in membrane proteins. Since this peak is in theregion corresponding to secondary structures, we investigated the influence ofsecondary structure ratio. We showed that secondary structure content has littleinfluence on this profile, while secondary structure collinearity in membraneproteins correlate with a stronger peak. Finally, we could further show that thepresence of this peak is linked to higher diffraction anisotropy. These resultsbring to light a specific diffraction of membrane protein crystals, which callsfor a specific handling by crystallographic software. It also brings anexplanation for investigators struggling with their anisotropic data.
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Internal Normal Mode Analysis Applied to RNA Flexibility and Conformational Changes.
- Journal : J Chem Inf Model
- 2023
- We investigated the capability of internal normal modes to reproduce RNAflexibility and predict observed RNA conformational changes and, notably, thoseinduced by the formation of RNA-protein and RNA-ligand complexes. Here, weextended our iNMA approach developed for proteins to study RNA molecules using asimplified representation of the RNA structure and its potential energy. Threedata sets were also created to investigate different aspects. Despite all theapproximations, our study shows that iNMA is a suitable method to take intoaccount RNA flexibility and describe its conformational changes opening the routeto its applicability in any integrative approach where these properties arecrucial.
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Rational Prediction of PROTAC-Compatible Protein-Protein Interfaces by Molecular Docking.
- Journal : J Chem Inf Model
- 2023
- Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands thatmediate the interaction between a protein target and an E3 ligase, resulting in aternary complex, whose interaction with the ubiquitination machinery leads totarget degradation. This technology is emerging as an exciting new avenue fortherapeutic development, with several PROTACs currently undergoing clinicaltrials targeting cancer. Here, we describe a general and computationallyefficient methodology combining restraint-based docking, energy-based rescoring,and a filter based on the minimal solvent-accessible surface distance to producePROTAC-compatible PPIs suitable for when there is no a priori known PROTACligand. In a benchmark employing a manually curated data set of 13 ternarycomplex crystals, we achieved an accuracy of 92% when starting from boundstructures and 77% when starting from unbound structures, respectively. Ourmethod only requires that the ligand-bound structures of the monomeric forms ofthe E3 ligase and target proteins be given to run, making it general, accurate,and highly efficient, with the ability to impact early-stage PROTAC-based drugdesign campaigns where no structural information about the ternary complexstructure is available.
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Conformational space exploration of cryo-EM structures by variability refinement.
- Journal : Biochim Biophys Acta Biomembr
- 2023
- Cryo-EM observation of biological samples enables visualization of sampleheterogeneity, in the form of discrete states that are separable, or continuousheterogeneity as a result of local protein motion before flash freezing.Variability analysis of this continuous heterogeneity describes the variancebetween a particle stack and a volume, and results in a map series describing thevarious steps undertaken by the sample in the particle stack. While thisobservation is absolutely stunning, it is very hard to pinpoint structuraldetails to elements of the maps. In order to bridge the gap between observationand explanation, we designed a tool that refines an ensemble of structures intoall the maps from variability analysis. Using this bundle of structures, it iseasy to spot variable parts of the structure, as well as the parts that are notmoving. Comparison with molecular dynamics simulations highlights the fact thatthe movements follow the same directions, albeit with different amplitudes.Ligand can also be investigated using this method. Variability refinement isavailable in the Phenix software suite, accessible under the program namephenix.varref.
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Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats
- Journal : Gut Microbes
- 2023
- Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo, 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.
Link to PubMed entry