Search Results (13)

Arginine plays a critical role in biomolecular interactions due to its guanidinium side chain, which enables multivalent electrostatic and hydrogen bonding contacts. In this study, atomistic molecular dynamics simulations were conducted across a broad concentration range (26–605 mM) to investigate the thermodynamic and structural features of arginine self-assembly in aqueous solution. Key observables—including hydrogen bond count, radius of gyration, contact number, and isobaric heat capacity—were analyzed to characterize emergent behavior. A three-regime aggregation pattern (dilute, cooperative, and saturated) was identified and quantitatively modeled using the Hill equation, revealing a non-linear transition in clustering behavior. Spatial analyses were supplemented with trajectory-based clustering and radial distribution functions. The heat capacity peak observed near 360 mM was interpreted as a thermodynamic signature of hydration rearrangement. Trajectory analyses utilized both GROMACS tools and the MDAnalysis library. While force field limitations and single-replica sampling are acknowledged, the results offer mechanistic insight into how arginine concentration modulates molecular organization—informing the understanding of biomolecular condensates, protein–nucleic acid complexes, and the design of functional supramolecular systems. The findings are in strong agreement with experimental observations from small-angle X-ray scattering and differential scanning calorimetry. Overall, this work establishes a cohesive framework for understanding amino acid condensation and reveals arginine’s concentration-dependent behavior as a model for weak, reversible molecular association. Full article

Both nanostructure and multivalency enhance the biological activities of antimicrobial peptides (AMPs), whose mechanism of action is cooperative. In addition, the efficacy of a particular AMP should benefit from a steady concentration at the local place of action and, therefore, from a slow release after a dynamic repository. In the context of emerging multi-resistant bacterial infections and the urgent need for novel and effective antimicrobial drugs, we tested these concepts through the engineering of four AMPs into supramolecular complexes as pharmacological entities. For that purpose, GWH1, T22, Pt5, and PaD, produced as GFP or human nidogen-based His-tagged fusion proteins, were engineered as self-assembling oligomeric nanoparticles ranging from 10 to 70 nm and further packaged into nanoparticle-leaking submicron granules. Since these materials slowly release functional nanoparticles during their time-sustained unpacking, they are suitable for use as drug depots in vivo. In this context, a particular AMP version (GWH1-NIDO-H6) was selected for in vivo validation in a zebrafish model of a complex bacterial infection. The GWH1-NIDO-H6-secreting protein granules are protective in zebrafish against infection by the multi-resistant bacterium Stenotrophomonas maltophilia, proving the potential of innovative formulations based on nanostructured and slowly released recombinant AMPs in the fight against bacterial infections. Full article

In recent years, the bottom-up approach has emerged as a powerful tool in the fabrication of functional nanomaterials through the self-assembly of nanoscale building blocks. The cues embedded at the molecular level provide a handle to control and direct the assembly of nano-objects to construct higher-order structures. Molecular recognition among the building blocks can assist their precise positioning in a predetermined manner to yield nano- and microstructures that may be difficult to obtain otherwise. A well-orchestrated combination of top-down fabrication and directed self-assembly-based bottom-up approach enables the realization of functional nanomaterial-based devices. Among the various available molecular recognition-based “host–guest” combinations, cyclodextrin-mediated interactions possess an attractive attribute that the interaction is driven in aqueous environments, such as in biological systems. Over the past decade, cyclodextrin-based specific host–guest interactions have been exploited to design and construct structural and functional nanomaterials based on cyclodextrin-coated metal nanoparticles. The focus of this review is to highlight recent advances in the self-assembly of cyclodextrin-coated metal nanoparticles driven by the specific host–guest interaction. Full article

Biomolecular condensation and phase separation are increasingly understood to play crucial roles in cellular compartmentalization and spatiotemporal regulation of cell machinery implicated in function and pathology. A key aspect of current research is to gain insight into the underlying physical mechanisms of these processes. Accordingly, concepts of soft matter and polymer physics, the thermodynamics of mixing, and material science have been utilized for understanding condensation mechanisms of multivalent macromolecules resulting in viscoelastic mesoscopic supramolecular assemblies. Here, we focus on two topological concepts that have recently been providing key mechanistic understanding in the field. First, we will discuss how percolation provides a network-topology-related framework that offers an interesting paradigm to understand the complex networking of dense ‘connected’ condensate structures and, therefore, their phase behavior. Second, we will discuss the idea of entanglement as another topological concept that has deep roots in polymer physics and important implications for biomolecular condensates. We will first review some historical developments and fundamentals of these concepts, then we will discuss current advancements and recent examples. Our discussion ends with a few open questions and the challenges to address them, hinting at unveiling fresh possibilities for the modification of existing knowledge as well as the development of new concepts relevant to condensate science. Full article

Vaccination has saved billions of human lives and has considerably reduced the economic burden associated with pandemic and endemic infectious diseases. Notwithstanding major advancements in recent decades, multitude diseases remain with no available effective vaccine. While subunit-based vaccines have shown great potential to address the safety concerns of live-attenuated vaccines, their limited immunogenicity remains a major drawback that still needs to be addressed for their use fighting infectious illnesses, autoimmune disorders, and/or cancer. Among the adjuvants and delivery systems for antigens, bacterial proteinaceous supramolecular structures have recently received considerable attention. The use of bacterial proteins with self-assembling properties to deliver antigens offers several advantages, including biocompatibility, stability, molecular specificity, symmetrical organization, and multivalency. Bacterial protein nanoassemblies closely simulate most invading pathogens, acting as an alarm signal for the immune system to mount an effective adaptive immune response. Their nanoscale architecture can be precisely controlled at the atomic level to produce a variety of nanostructures, allowing for infinite possibilities of organized antigen display. For the bottom-up design of the proteinaceous antigen delivery scaffolds, it is essential to understand how the structural and physicochemical properties of the nanoassemblies modulate the strength and polarization of the immune responses. The present review first describes the relationships between structure and the generated immune responses, before discussing potential and current clinical applications. Full article

Supramolecular combination therapy adopts supramolecular materials to design intelligent drug delivery systems with different strategies for cancer treatments. Thereinto, macrocyclic supramolecular materials play a crucial role in encapsulating anticancer drugs to improve anticancer efficiency and decrease toxicity towards normal tissue by host–guest interaction. In general, chemotherapy is still common therapy for solid tumors in clinics. However, supramolecular combination therapy can overcome the limitations of the traditional single-drug chemotherapy in the laboratory findings. In this review, we summarized the combination chemotherapy, photothermal chemotherapy, and gene chemotherapy based on macrocyclic supramolecular materials. Finally, the application prospects in supramolecular combination therapy are discussed. Full article

Lectins, carbohydrate-binding proteins, are attractive biomolecules for medical and biotechnological applications. Many lectins have multiple carbohydrate recognition domains (CRDs) and strongly bind to specific glycans through multivalent binding effect. In our previous study, protein nano-building blocks (PN-blocks) were developed to construct self-assembling supramolecular nanostructures by linking two oligomeric proteins. A PN-block, WA20-foldon, constructed by fusing a dimeric four-helix bundle de novo protein WA20 to a trimeric foldon domain of T4 phage fibritin, self-assembled into several types of polyhedral nanoarchitectures in multiples of 6-mer. Another PN-block, the extender PN-block (ePN-block), constructed by tandemly joining two copies of WA20, self-assembled into cyclized and extended chain-type nanostructures. This study developed novel functional protein nano-building blocks (lectin nano-blocks) by fusing WA20 to a dimeric lectin, Agrocybe cylindracea galectin (ACG). The lectin nano-blocks self-assembled into various oligomers in multiples of 2-mer (dimer, tetramer, hexamer, octamer, etc.). The mass fractions of each oligomer were changed by the length of the linkers between WA20 and ACG. The binding avidity of the lectin nano-block oligomers to glycans was significantly increased through multivalent effects compared with that of the original ACG dimer. Lectin nano-blocks with high avidity will be useful for various applications, such as specific cell labeling. Full article

Membraneless organelles are non-stoichiometric supramolecular structures in the micron scale. These structures can be quickly assembled/disassembled in a regulated fashion in response to specific stimuli. Membraneless organelles contribute to the spatiotemporal compartmentalization of the cell, and they are involved in diverse cellular processes often, but not exclusively, related to RNA metabolism. Liquid-liquid phase separation, a reversible event involving demixing into two distinct liquid phases, provides a physical framework to gain insights concerning the molecular forces underlying the process and how they can be tuned according to the cellular needs. Proteins able to undergo phase separation usually present a modular architecture, which favors a multivalency-driven demixing. We discuss the role of low complexity regions in establishing networks of intra- and intermolecular interactions that collectively control the phase regime. Post-translational modifications of the residues present in these domains provide a convenient strategy to reshape the residue–residue interaction networks that determine the dynamics of phase separation. Focus will be placed on those proteins with low complexity domains exhibiting a biased composition towards the amino acid methionine and the prominent role that reversible methionine sulfoxidation plays in the assembly/disassembly of biomolecular condensates. Full article

FGFRs are cell surface receptors that, when activated by specific FGFs ligands, transmit signals through the plasma membrane, regulating key cellular processes such as differentiation, division, motility, metabolism and death. We have recently shown that the modulation of the spatial distribution of FGFR1 at the cell surface constitutes an additional mechanism for fine-tuning cellular signaling. Depending on the multivalent, engineered ligand used, the clustering of FGFR1 into diverse supramolecular complexes enhances the efficiency and modifies the mechanism of receptor endocytosis, alters FGFR1 lifetime and modifies receptor signaling, ultimately determining cell fate. Here, we present a novel approach to generate multivalent FGFR1 ligands. We functionalized FGF1 for controlled oligomerization by developing N- and C-terminal fusions of FGF1 with the Fc fragment of human IgG1 (FGF1-Fc and Fc-FGF1). As oligomerization scaffolds, we employed GFPpolygons, engineered GFP variants capable of well-ordered multivalent display, fused to protein G to ensure binding of Fc fragment. The presented strategy allows efficient assembly of oligomeric FGFR1 ligands with up to twelve receptor binding sites. We show that multivalent FGFR1 ligands are biologically active and trigger receptor clustering on the cell surface. Importantly, the approach described in this study can be easily adapted to oligomerize alternative growth factors to control the activity of other cell surface receptors. Full article

Cyclodextrins (CDs) have long occupied a prominent position in most pharmaceutical laboratories as “off-the-shelve” tools to manipulate the pharmacokinetics of a broad range of active principles, due to their unique combination of biocompatibility and inclusion abilities. The development of precision chemical methods for their selective functionalization, in combination with “click” multiconjugation procedures, have further leveraged the nanoscaffold nature of these oligosaccharides, creating a direct link between the glyco and the nano worlds. CDs have greatly contributed to understand and exploit the interactions between multivalent glycodisplays and carbohydrate-binding proteins (lectins) and to improve the drug-loading and functional properties of nanomaterials through host–guest strategies. The whole range of capabilities can be enabled through self-assembly, template-assisted assembly or covalent connection of CD/glycan building blocks. This review discusses the advancements made in this field during the last decade and the amazing variety of functional glyconanomaterials empowered by the versatility of the CD component. Full article

Life-inspired protein supramolecular assemblies have recently attracted considerable attention for the development of next-generation vaccines to fight against infectious diseases, as well as autoimmune diseases and cancer. Protein self-assembly enables atomic scale precision over the final architecture, with a remarkable diversity of structures and functionalities. Self-assembling protein nanovaccines are associated with numerous advantages, including biocompatibility, stability, molecular specificity and multivalency. Owing to their nanoscale size, proteinaceous nature, symmetrical organization and repetitive antigen display, protein assemblies closely mimic most invading pathogens, serving as danger signals for the immune system. Elucidating how the structural and physicochemical properties of the assemblies modulate the potency and the polarization of the immune responses is critical for bottom-up design of vaccines. In this context, this review briefly covers the fundamentals of supramolecular interactions involved in protein self-assembly and presents the strategies to design and functionalize these assemblies. Examples of advanced nanovaccines are presented, and properties of protein supramolecular structures enabling modulation of the immune responses are discussed. Combining the understanding of the self-assembly process at the molecular level with knowledge regarding the activation of the innate and adaptive immune responses will support the design of safe and effective nanovaccines. Full article

Discotic molecules, which self-assemble in water into columnar supramolecular polymers, emerged as an alternative platform for the organization of proteins. Here, a monovalent discotic decorated with one single biotin was synthesized to study the self-assembling multivalency of this system in regard to streptavidin. Next to tetravalent streptavidin, monovalent streptavidin was used to study the protein assembly along the supramolecular polymer in detail without the interference of cross-linking. Upon self-assembly of the monovalent biotinylated discotics, multivalent proteins can be assembled along the supramolecular polymer. The concentration of discotics, which influences the length of the final polymers at the same time dictates the amount of assembled proteins. Full article

The supramolecular layer-by-layer assembly of 3D multicomponent nanostructures of nanoparticles is demonstrated. Nanoimprint lithography (NIL) was used as the patterning tool for making patterned β-cyclodextrin (CD) self-assembled monolayers (SAMs) and for the confinement of nanoparticles on the substrate. A densely packed and multilayered nanoparticle structure was created by alternating assembly steps of complementary guest- (Fc-SiO₂, 60 nm) and host-functionalized (CD-Au, 3 nm) nanoparticles. The effects induced by the order of the nanoparticle assembly steps, going from large to small and from small to large nanoparticles by using Fc-SiO₂, CD-Au, and CD-SiO₂ (350 nm) nanoparticles, were compared. AFM height profiles revealed that the specific supramolecular assembly of nanoparticles was self-limited, i.e. one nanoparticle layer per assembly step, allowing the control over the thickness of the supramolecular hybrid nanostructure by choosing the size of the nanoparticles, irrespective of the core material of the nanoparticles. The roughness of structure, observed by AFM imaging of the top layer, was directly influenced by the size and packing of the underlying nanoparticle layers. Full article