Abstract Lectin LecA is a virulence factor of Pseudomonas aeruginosa involved in lung injury, mortality, and cellular invasion. Ligands competing with human glycoconjugates for binding are thus promising candidates to counteract P. infections. We have identified novel divalent ligand from focused galactoside(Gal)‐conjugate array which binds very high affinity ( K d =82 n M ). Crystal structures complexed the together modeling studies confirmed its ability chelate two sites LecA. The lowers...

Abstract Mammalian sense of smell is triggered by interaction between odorant molecules and a class proteins, called olfactory receptors (ORs). These receptors, expressed at the surface sensory neurons, encode myriad distinct odors via sophisticated activation pattern. However, determining molecular recognition spectrum ORs remains major challenge. The Molecule to Olfactory Receptor database (M2OR, https://m2or.chemsensim.fr/) provides curated data that allows an easy exploration current...

Abstract Life on Earth employs chiral amino acids in stereochemical l -form, but the cause of molecular symmetry breaking remains unknown. Chiroptical properties – expressed circular dichroism (CD) have been previously investigated solid and solution phase. However, both environments distort intrinsic charge distribution associated with CD transitions. Here we report anisotropy spectra recorded gas phase, where any asymmetry is solely determined by genuine electromagnetic transition moments....

Histo-blood group epitopes are fucosylated branched oligosaccharides with well-defined conformations in solution that recognized by receptors, such as lectins from pathogens. We report here the results of a series experimental and computational endeavors revealing unusual distortion histo-blood antigens bacterial fungal lectins. The Lewis x trisaccharide adopts rigid closed conformation solution, while crystallography molecular dynamics reveal several higher energy open when bound to...

Deciphering how an odorant activates receptor (OR) and changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site-directed mutagenesis functional assays with computational modeling has been used explore the signaling mechanics OR7D4. In this OR, a genetic polymorphism affects perception androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly observations for other G-protein-coupled...

Abstract Systematic enrichments of l -amino acids in meteorites is a strong indication that biological homochirality originated beyond Earth. Although still unresolved, stellar UV circularly polarized light (CPL) the leading hypothesis to have caused symmetry breaking space. This involves differential absorption left- and right-CPL, phenomenon called circular dichroism, which enables chiral discrimination. Here we unveil coherent chiroptical spectra thin films isovaline enantiomers, first...

Odorant receptors (ORs) are main actors of the insects peripheral olfactory system, making them prime targets for pest control through disruption. Traditional methods employed in context chemical ecology identifying OR ligands rely on analyzing compounds present insect's environment or screening molecules with structures similar to known ligands. However, these approaches can be time-consuming and constrained by limited space they explore. Recent advances structural understanding, coupled...

Recent advances in glycobiology revealed the essential role of lectins for deciphering glycocode by specific recognition carbohydrates. Integrated multiscale approaches are needed characterizing lectin specificity: combining on one hand high-throughput analysis glycan array experiments and systematic molecular docking oligosaccharide libraries other detailed lectin/oligosaccharide interaction x-ray crystallography, microcalorimetry free energy calculations. The LecB from Pseudomonas...

Abstract A joint approach combining free‐energy calculations and calcium‐imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding ten odorants was computed by means molecular‐dynamics simulations. This state function allows separating experimentally determined eight agonists from two non‐agonists. study constitutes a proof‐of‐principle for computational deorphanization receptors.

G protein–coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in nonolfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles promiscuity specificity. Using site-directed mutagenesis molecular modeling, constructed 3D models ECL2 forms lid over...

In numerous insects, the olfactory receptor family forms a unique class of heteromeric cation channels. Recent progress in resolving odorant structures offers unprecedented opportunities for deciphering their molecular mechanisms ligand recognition. Unexpectedly, these apo or ligand-bound states did not reveal pathway taken by ligands between extracellular space and deep internal cavities. By combining modeling with electrophysiological recordings, we identified amino acids involved dynamic...

Abstract Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in infection process. Inhibition both with carbohydrate‐derived molecules can reduce biofilm formation to restore susceptibility. Here, we focused on non‐carbohydrate inhibitors for explore new avenues lectin inhibition. From a screening cascade obtained one experimentally confirmed hit, catechol, belonging well‐known PAINS compounds. Rigorous...

Abstract Lectin LecA is a virulence factor of Pseudomonas aeruginosa involved in lung injury, mortality, and cellular invasion. Ligands competing with human glycoconjugates for binding are thus promising candidates to counteract P. infections. We have identified novel divalent ligand from focused galactoside(Gal)‐conjugate array which binds very high affinity ( K d =82 n M ). Crystal structures complexed the together modeling studies confirmed its ability chelate two sites LecA. The lowers...

ABSTRACT A joint approach that combines molecular modelling and fluorescence spectroscopy is used to study the affinity of an odorant binding protein towards various molecules. We focus on capability rank odorants according their with this protein, which involved in sense smell. Although ligand‐based approaches are unable propose accurate model attending strength bond odorant‐binding receptor‐based structures considering either static or dynamic structure perform equally discriminate between...

Site Directed Spin Labeling (SDSL) combined with EPR spectroscopy is a very powerful approach to investigate structural transitions in proteins particular flexible or even disordered ones. Conventional spin labels are based on nitroxide derivatives leading classical 3-line spectra whose spectral shapes indicative of the environment and thus constitute good reporters modifications. However, similarity these precludes probing two regions protein partner simultaneously. To overcome limitation...

We have investigated O₂ and H₂ transport across a NiFe hydrogenase at the atomic scale by means of computational methods. The Wild Type protein has been compared with V74Q mutant. Two distinct methodologies applied to study gas access active site. Temperature locally enhanced sampling simulations emphasized importance dynamics on diffusion. diffusion free energy profiles, obtained umbrella sampling, are in agreement known kinetic data show that mutant, inhibition process is lowered from both...

Hydrogenases are promising candidates for the catalytic production of green energy by means biological ways. The major impediment to such a is rooted in their inhibition under aerobic conditions. In this work, we model dioxygen migration rates mutants hydrogenase Desulfovibrio fructusovorans. approach relies on calculation whole potential mean force O2 within wild-type as well V74M, V74F, and V74Q mutant channels. three free-energy barriers along entire pathway converted into chemical...

Mammals recognize chemicals in the air via G protein-coupled odorant receptors (ORs). In addition to their orthosteric binding site, other segments of these modulate ligand recognition. Focusing on human hOR1A1, which is considered prototypical class II ORs, we used a combination molecular modeling, site-directed mutagenesis, and vitro functional assays. We showed that third extracellular loop ORs (ECL3) contributes recognition receptor activation. Indeed, mutations ECL3 differential effects...

Abstract Deciphering how an odorant activates receptor (OR) and changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site‐directed mutagenesis functional assays with computational modeling has been used explore the signaling mechanics OR7D4. In this OR, a genetic polymorphism affects perception androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly observations for other G‐protein‐coupled...

The mechanisms of odor discrimination are based on the differential interactions odorant molecules with olfactory receptors (ORs). biohybrid sensors described so far using ORs show selectivity towards specific versus non-specific binding. Here we disclose a method that enables modulation capacitive response receptor allows differentiation three high-affinity hOR1A1 agonists. We performed voltammetry and impedance measurements selectively immobilized gold electrode in absence presence Binding...