Dataset Information

Giant Polymersome Protocells Dock with Virus Particle Mimics via Multivalent Glycan-Lectin Interactions.

ABSTRACT: Despite the low complexity of their components, several simple physical systems, including microspheres, coacervate droplets and phospholipid membrane structures (liposomes), have been suggested as protocell models. These, however, lack key cellular characteristics, such as the ability to replicate or to dock with extracellular species. Here, we report a simple method for the de novo creation of synthetic cell mimics in the form of giant polymeric vesicles (polymersomes), which are capable of behavior approaching that of living cells. These polymersomes form by self-assembly, under electroformation conditions, of amphiphilic, glycosylated block copolymers in aqueous solution. The glycosylated exterior of the resulting polymeric giant unilamellar vesicles (GUVs) allows their selective interaction with carbohydrate-binding receptor-functionalized particles, in a manner reminiscent of the cell-surface docking of virus particles. We believe that this is the first example of a simple protocell model displaying cell-like behavior through a native receptor-ligand interaction.

SUBMITTER: Kubilis A

PROVIDER: S-EPMC5006173 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Giant Polymersome Protocells Dock with Virus Particle Mimics via Multivalent Glycan-Lectin Interactions.

Kubilis Artur A Abdulkarim Ali A Eissa Ahmed M AM Cameron Neil R NR

Scientific reports 20160831

Despite the low complexity of their components, several simple physical systems, including microspheres, coacervate droplets and phospholipid membrane structures (liposomes), have been suggested as protocell models. These, however, lack key cellular characteristics, such as the ability to replicate or to dock with extracellular species. Here, we report a simple method for the de novo creation of synthetic cell mimics in the form of giant polymeric vesicles (polymersomes), which are capable of be ...[more]

PMID: 27576579

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Project description:Lectin-glycan interactions facilitate inter- and intracellular communication in many processes including protein trafficking, host-pathogen recognition, and tumorigenesis promotion. Specific recognition of glycans by lectins is also the basis for a wide range of applications in areas including glycobiology research, cancer screening, and antiviral therapeutics. To provide a better understanding of the determinants of lectin-glycan interaction specificity and support such applications, this study comprehensively investigates specificity-conferring features of all available lectin-glycan complex structures. Systematic characterization, comparison, and predictive modeling of a set of 221 complementary physicochemical and geometric features representing these interactions highlighted specificity-conferring features with potential mechanistic insight. Univariable comparative analyses with weighted Wilcoxon-Mann-Whitney tests revealed strong statistical associations between binding site features and specificity that are conserved across unrelated lectin binding sites. Multivariable modeling with random forests demonstrated the utility of these features for predicting the identity of bound glycans based on generalized patterns learned from non-homologous lectins. These analyses revealed global determinants of lectin specificity, such as sialic acid glycan recognition in deep, concave binding sites enriched for positively charged residues, in contrast to high mannose glycan recognition in fairly shallow but well-defined pockets enriched for non-polar residues. Focused fine specificity analysis of hemagglutinin interactions with human-like and avian-like glycans uncovered features representing both known and novel mutations related to shifts in influenza tropism from avian to human tissues. As the approach presented here relies on co-crystallized lectin-glycan pairs for studying specificity, it is limited in its inferences by the quantity, quality, and diversity of the structural data available. Regardless, the systematic characterization of lectin binding sites presented here provides a novel approach to studying lectin specificity and is a step towards confidently predicting new lectin-glycan interactions.

Project description:Multivalent lectin-glycan interactions (MLGIs) are widespread and vital for biology, making them attractive therapeutic targets. Unfortunately, the structural and biophysical mechanisms of several key MLGIs remain poorly understood, limiting our ability to design spatially matched glycoconjugates as potential therapeutics against specific MLGIs. We have recently demonstrated that natural oligomannose-coated nanoparticles are powerful probes for MLGIs. They can provide not only quantitative affinity and binding thermodynamic data but also key structural information (e.g, binding site orientation and mode) useful for designing glycoconjugate therapeutics against specific MLGIs. Despite success, how designing parameters (e.g., glycan type, density, and scaffold size) control their MLGI biophysical and antiviral properties remains to be elucidated. A synthetic pseudodimannose (psDiMan) ligand has been shown to selectively bind to a dendritic cell surface tetrameric lectin, DC-SIGN, over some other multimeric lectins sharing monovalent mannose specificity but having distinct cellular functions. Herein, we display psDiMan polyvalently onto gold nanoparticles (GNPs) of varying sizes (e.g., ∼5 and ∼13 nm, denoted as G5- and G13 psDiMan hereafter) to probe how the scaffold size and glycan display control their MLGI properties with DC-SIGN and the closely related lectin DC-SIGNR. We show that G5/13 psDiMan binds strongly to DC-SIGN, with sub-nM K ds, with affinity being enhanced with increasing scaffold size, whereas they show apparently no or only weak binding to DC-SIGNR. Interestingly, there is a minimal, GNP-size-dependent, glycan density threshold for forming strong binding with DC-SIGN. By combining temperature-dependent affinity and Van't Hoff analyses, we have developed a new GNP fluorescence quenching assay for MLGI thermodynamics, revealing that DC-SIGN-Gx-psDiMan binding is enthalpy-driven, with a standard binding ΔH 0 of ∼ -95 kJ mol-1, which is ∼4-fold that of the monovalent binding and is comparable to that measured by isothermal titration calorimetry. We further reveal that the enhanced DC-SIGN affinity with Gx-psDiMan with increasing GNP scaffold size is due to reduced binding entropy penalty and not due to enhanced favorable binding enthalpy. We further show that DC-SIGN binds tetravalently to a single Gx-psDiMan, irrespective of the GNP size, whereas DC-SIGNR binding is dependent on GNP size, with no apparent binding with G5, and weak cross-linking with G13. Finally, we show that Gx-psDiMans potently inhibit DC-SIGN-dependent augmentation of cellular entry of Ebola pseudoviruses with sub-nM EC50 values, whereas they exhibit no significant (for G5) or weak (for G13) inhibition against DC-SIGNR-augmented viral entry, consistent to their MLGI properties with DC-SIGNR in solution. These results have established Gx-psDiMan as a versatile new tool for probing MLGI affinity, selectivity, and thermodynamics, as well as GNP-glycan antiviral properties.

Dataset Information

Giant Polymersome Protocells Dock with Virus Particle Mimics via Multivalent Glycan-Lectin Interactions.

Publications

Giant Polymersome Protocells Dock with Virus Particle Mimics via Multivalent Glycan-Lectin Interactions.

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