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Fundamental insight into the interaction between a lithium salt and an inorganic filler for ion mobility using a synergic theoretical-experimental approach |
Protein-Protein Interface Topology as a Predictor of Secondary Structure and Molecular Function Using Convolutional Deep Learning |
New biobased-zwitterionic ionic liquids: efficiency and biocompatibility for the development of sustainable biorefinery processes |
Curvature as a Collective Coordinate in Enhanced Sampling Membrane Simulations |
Ironing out pyoverdine’s chromophore structure: serendipity or design? |
Impact of iron coordination isomerism on pyoverdine recognition by the FpvA membrane transporter of Pseudomonas aeruginosa |
The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation |
Optimizing the Multivalent Binding of the Bacterial Lectin LecA by Glycopeptide Dendrimers for Therapeutic Purposes |
Cooperative DNA Recognition Modulated by an Interplay between Protein-Protein Interactions and DNA-Mediated Allostery Pluripotent stem cells can give rise to all somatic lineages. When taken out of the context of the embryo they can be maintained and for this a core transcriptional regulatory circuitry is crucial. OCT4 and SOX2, two factors of this network, are also critical for the induction of pluripotency in somatic cells. In pluripotent cells, OCT4 and SOX2 associate on DNA regulatory regions, enhancing or modifying each other's sequence specificity. In contrast, in the early stages during induction of pluripotency, it was proposed that OCT4 explores the genome independent of SOX2. Here we report the mechanism by which SOX2 influences the orientation, dynamics, and unbinding free energy profile of OCT4. This involves an interplay of protein-protein interactions and DNA-mediated allostery. We consider that this mechanism enables OCT4 to use its DNA binding domains and the interaction partners available in a certain biological context to access alternative genome exploration routes. This study enhances the understanding of the context specific function of OCT4 and provides a general perspective on how DNA-binding cooperativity is modulated by different types of interactions. http://dx.doi.org/10.1371/journal.pcbi.1004287 |
Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations |
The present paper aims at providing a fundamental insight into the interaction between a lithium salt and an inorganic filler in a perspective of lithium mobility. Through a synergistic approach, coupling experimental results and molecular dynamics simulations, the influence of the surface chemical state of the nanosilica Stöber-type on the dissociation of LiTFSI and its impact on the lithium conduction properties are studied. For this purpose, the surface modification of silica nanoparticles was performed by different methods such as calcination, lithiation and capping with organosilane. The impact of the surface modification on the dissociation of the lithium salt is further investigated by electrochemical impedance spectroscopy after impregnation of the material with a defined amount of lithium salt. The combined experimental and in silico analyses of the results, performed for the first time on such systems, allow a detailed understanding of the interaction between the salt and the support and should prove itself useful for the future design of hybrid polymer electrolytes in new generation batteries.
To power the specific recognition and binding of protein partners into functional complexes, a wealth of information about the structure and function of the partners is necessarily encoded into the global shape of protein-protein interfaces and their local topological features. To identify whether this is the case, this study uses convolutional deep learning methods (typically leveraged for 2D image recognition) on 3D voxel representations of protein-protein interfaces colored by burial depth. A novel two-stage network fed with voxelizations of each interface at two distinct resolutions achieves balance between performance and computational cost. From the shape of the interfaces, the network tries to predict the presence of secondary structure motifs at the interface and the molecular function of the corresponding complex. Secondary structure and certain classes of function are found to be very well predicted, validating the hypothesis that interface shape is a conveyor of higher-level information. Interface patterns triggering the recognition of specific classes are also identified and described.
A new family of biobased-zwitterionic ionic liquids (ZILs) have been synthesized starting from the renewable resource l-histidine natural amino acid and varying the lengths of the alkyl chains. These ZIL derivatives were firstly studied for their biocompatibility with different microorganisms including bacteria, molds and yeast. The obtained MIC values indicated that all the microorganisms were 5 to 25 times more tolerant to ZIL derivatives than the robust 1-ethyl-3-methylimidazolium acetate [C2mim][OAc] used as a reference. Modeling studies also revealed that the presence of the cation and the anion on the same skeleton together with the length of the N-alkyl chain would govern the biocompatibility of these neoteric solvents. Among the different synthesized ZILs, the N,N′-diethyl derivative has been demonstrated to be a suitable eco-alternative to the classically used [C2mim][OAc] for efficient pretreatment of harwood sawdust leading to a significant improvement of enzymatic saccharification. In addition, with up to a 5% w/v concentration in the culture medium, ZILs did not induce deleterious effects on fermentative yeast growth nor ethanol production.
The plasticity of membranes plays an important functional role in cells, cell components, and micelles, where bending, budding, and remodeling implement numerous recognition and communication processes. Comparatively, molecular simulation methods to induce, control, and quantitatively characterize such deformations remain scarce. This work defines a novel collective coordinate associated with membrane bending, which strives to combine realism (by preserving the notion of local atomic curvatures) and low computational cost (allowing its evaluation at every time step of a molecular dynamics simulation). Enhanced sampling simulations along this conformational coordinate provide convenient access to the underlying bending free energy landscape. To showcase its potential, the method is applied to three state-of-the-art problems: the determination of the bending free energy landscape of a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) bilayer, the formation of a POPE liposome, and the study of the influence of the Pseudomonas quinolone signal on the budding of Gram-negative bacterial outer membranes.
Pyoverdines are Pseudomonas aeruginosa’s primary siderophores. These molecules, composed of a fluorescent chromophore attached to a peptide chain of 6–14 amino acids, are synthesized by the bacterium to scavenge iron (essential to its survival and growth) from its environment. Hijacking the siderophore pathway to use pyoverdine–antibiotic compounds in a Trojan horse approach has shown promise but remains very challenging because of the synthetic efforts involved. Indeed, both possible approaches (grafting an antibiotic on pyoverdine harvested from Pseudomonas or designing a total synthesis route) are costly, time-consuming and low-yield tasks. Designing comparatively simple analogs featuring the salient properties of the original siderophore is thus crucial for the conception of novel antibiotics to fight bacterial resistance. In this work, we focus on the replacement of the pyoverdine chromophore, a major roadblock on the synthetic pathway. We propose three simpler analogs and evaluate their ability to complex iron and interact with the FpvA transporter using molecular modeling techniques. Based on these results, we discuss the role of the native chromophore’s main features (polycyclicity, positive charge, flexibility) on pyoverdine’s ability to bind iron and be recognized by membrane transporter FpvA and propose guidelines for the design of effective synthetic siderophores.
Pyoverdines, the primary siderophores of Pseudomonas bacteria, scavenge the iron essential to bacterial life in the outside medium and transport it back into the periplasm. Despite their relative simplicity, pyoverdines feature remarkably flexible recognition characteristics whose origins at the atomistic level remain only partially understood: the ability to bind other metals than ferric iron, the capacity of outer membrane transporters to recognize and internalize noncognate pyoverdines from other pseudomonads... One of the less examined factors behind this polymorphic recognition lies in the ability for pyoverdines to bind iron with two distinct chiralities, at the cost of a conformational switch. Herein, we use free energy simulations to study how the stereochemistry of the iron chelating groups influences the structure and dynamics of two common pyoverdines and impacts their recognition by the FpvA membrane transporter of P. aeruginosa. We show that conformational preferences for one metal binding chirality over the other, observed in solution depending on the nature of the pyoverdine, are canceled out by the FpvA transporter, which recognizes both chiralities equally well for both pyoverdines under study. However, FpvA discriminates between pyoverdines by altering the kinetics of stereoisomer interconversion. We present structural causes of this intriguing recognition mechanism and discuss its possible significance in the context of the competitive scavenging of iron.
2-Oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the post-reaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.
Bacterial lectins are nonenzymic sugar-binding proteins involved in the formation of biofilms and the onset of virulence. The weakness of individual sugar-lectin interactions is compensated by the potentially large no. of simultaneous copies of such contacts, resulting in high overall sugar-lectin affinities and marked specificities. Therapeutic compds. functionalized with sugar residues can compete with the host glycans for binding to lectins only if they are able to take advantage of this multivalent binding mechanism. Glycopeptide dendrimers, featuring treelike topologies with sugar moieties at their leaves, have already shown great promise in this regard. However, optimizing the dendrimers' amino acid sequence is necessary to match the dynamics of the lectin active sites with that of the multivalent ligands. This work combines long-time-scale coarse-grained simulations of dendrimers and lectins with a reasoned exploration of the dendrimer sequence space in an attempt to suggest sequences that could maximize multivalent binding to the galactose-specific bacterial lectin LecA. These candidates are validated by simulations of mixed dendrimer/lectin solns., and the effects of the dendrimers on lectin dynamics are discussed. This approach is an attractive first step in the conception of therapeutic compds. based on the dendrimer scaffold and contributes to the understanding of the various classes of multivalency that underpin the ubiquitous "sugar code". 
The Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism.