Macromolecular Self-assembly Research Articles

Self-assembly of architected macromolecules: Bridging a gap between experiments and simulations

Macromolecular self-assembly is essential in life and interfacial science. A macromolecule consisting of chemically distinct components tends to self-assemble in a selective solvent to minimize the exposure of the solvophobic segments to the medium while the solvophilic segments adopt extended conformations. While micelles composed of linear block copolymers represent classic examples of such solution assembly, recent interest focuses on the self-assembly of complex macromolecules with nonlinear architectures, such as star, graft, and bottlebrush. Such macromolecules include several to hundreds of polymer chains covalently tied to a core and a backbone. The pre-programmed, non-exchangeable chain arrangement makes a huge difference in their self-assembly. The field has witnessed tremendous advances in synthetic methodologies to construct the desired architectures, leading to discoveries of exotic self-assembly behavior. Thanks to the rapid evolution of computing power, computer simulation has also been an emerging and complementary approach for understanding the association mechanism and further predicting the self-assembling morphologies. However, simulating the self-assembly of architected macromolecules has posed a challenge as a huge number of objects should be included in the simulations. Comparing experimental results with simulations is not always straightforward, as synthetic routes to well-defined model systems with systematically controlled structural parameters are not often available. In this manuscript, we propose to bridge a gap between experiments and simulations in self-assembly of architected macromolecules. We focus on the key articles in this area reporting experimental evidence and simulation details and also cover recent examples in the literature. We start with discussing simulation methodologies applicable to investigate solution self-assembly across multiple levels of chemical resolution from all-atom to particle dynamics. Then, we delve into topological design, synthesis, and simulation of nonlinear macromolecules, including dendritic/star, network, and graft/bottlebrush polymers, to understand the architectural effect on the self-assembly behavior. We expand our discourse to embrace recent advances toward realizing more complex systems. For example, self-assembly in the presence of strong Coulombic interactions, such as in the case of polyelectrolytes, geometric constraints, and other components in solutions, exemplified by inorganic fillers, are introduced. Finally, the challenges and perspectives are discussed in the final section of the manuscript.

Ultrafast, Robust, and Reversible Self-Assembled Nanofibers via Thiolactone Chemistry Strategy.

Self-assembly in supramolecular chemistry is crucial for nanostructure creation but faces challenges like slow speeds and lack of reversibility. In this study, a novel comb-like polymer poly(amide sulfide) (PAS) based on thiolactone chemistry is reported, which rapidly self-assemble into stable nanofibers, offering excellent robustness and reversibility in the self-assembled structure. The PAS backbone contains pairs of amide bonds, each linked to an alkyl side chain in a controlled 2:1 ratio. The polymer rapidly forms fibrillar micelles driven by the hydrophobic side chains and then undergoes hydrogen-bonded cross-linking between the main-chain amide bonds to form stable nanofibers. N, N-dimethylacetamide/LiCl solution allows for reversible regulation of nanofiber self-assembly, without altering the fiber properties. It is anticipated that this line of research will enrich the field of macromolecular self-assembly with important advances toward the realization of ultrafast, robust, and reversible self-assembly systems.

Large language models design sequence-defined macromolecules via evolutionary optimization

We demonstrate the ability of a large language model to perform evolutionary optimization for materials discovery. Anthropic’s Claude 3.5 model outperforms an active learning scheme with handcrafted surrogate models and an evolutionary algorithm in selecting monomer sequences to produce targeted morphologies in macromolecular self-assembly. Utilizing pre-trained language models can potentially reduce the need for hyperparameter tuning while offering new capabilities such as self-reflection. The model performs this task effectively with or without context about the task itself, but domain-specific context sometimes results in faster convergence to good solutions. Furthermore, when this context is withheld, the model infers an approximate notion of the task (e.g., calling it a protein folding problem). This work provides evidence of Claude 3.5’s ability to act as an evolutionary optimizer, a recently discovered emergent behavior of large language models, and demonstrates a practical use case in the study and design of soft materials.

Self-Assembly of Glycolipid Epimers: Their Supramolecular Morphology Control and Immunoactivation Function.

Although advances have been made in carbohydrate-based macromolecular self-assembly, harnessing epimers of carbohydrates to perform molecular assembly and further investigating the properties of supramolecular materials remain little explored. Herein, two classes of stereoisomeric glycolipid amphiphiles based on d-N-acetylgalactosamine (GalNAc) are reported, and they can aggregate into ribbon-like structures in the aqueous solution due to amphiphilic property, which allow to obtain glycocalyx-mimicking supramolecular materials. The subtle distinction in glycoside configuration of GalNAc-α-SSA and GalNAc-β-SSA dictates the different molecular packing in self-assembled structures. Since driven by the distinguishing carbohydrate-carbohydrate interactions, the ribbon-like architectures transform into spherical nanostructures via mixing GalNAc-α-SSA and GalNAc-β-SSA. The resulting spherical micelles fabricated by blending glycolipid epimers can potentiate the macrophage- and dendritic cell-mediated immune responses in vitro. Such glycolipid epimers will pave the way to create glycocalyx-mimicking immune modulators by incorporating stereochemistry into supramolecular self-assembly.

Sequence-Isomerism-Controlled Macromolecular Self-Assembly in Dendritic Rod-Like Molecules.

Although in Nature sequence control is widely adopted to tune the structure and functions of biomacromolecules, it remains challenging and largely unexplored in synthetic macromolecular systems due to the difficulties in a precision synthesis, which impedes the understanding of the structure-property relationship in macromolecular sequence isomerism. Herein, we report the sequence-controlled macromolecular self-assembly enabled by a pair of rationally designed isomeric dendritic rod-like molecules. With an identical chemical formula and molecular topology, the molecular solid angle of the dendron isomers was determined by the sequence of the rod building blocks tethered with side chains of different lengths. As a result, entirely different supramolecular motifs of discs and spheres were generated, which were further packed into a hexagonally packed cylinder phase and a dodecagonal quasicrystalline sphere phase, respectively. Given the efficient synthesis and modular structural variations, it is believed that the sequence-isomerism-controlled self-assembly in dendritic rod-like molecules might provide a unique avenue toward rich nanostructures in synthetic macromolecules.

Improved Solid Electrolyte Conductivity via Macromolecular Self-Assembly: From Linear to Star Comb-like P(S-co-BzMA)-b-POEGA Block Copolymers.

Star block copolymer electrolytes with a lithium-ion conducting phase are investigated in the present work to assess the influence of this complex architecture compared to that of the linear one, on both, bulk morphology and ionic conductivity. For that purpose, the controlled synthesis of a series of poly(styrene-co-benzyl methacrylate)-b-poly[oligo(ethylene glycol) methyl ether acrylate] [P(S-co-BzMA)-b-POEGA] block copolymers (BCPs) by reversible addition-fragmentation transfer polymerization was performed from either a monofunctional or a tetrafunctional chain transfer agent containing trithiocarbonate groups. We emphasized how a small amount of styrene (6 mol %) drastically improved the control of the RAFT polymerization of benzyl methacrylate mediated by the tetrafunctional chain transfer agent. Transmission electron microscopy and small-angle X-ray scattering demonstrated a clear segregation of the BCPs in the presence of lithium salt. Interestingly, the star BCPs gave rise to highly ordered lamellar structures as compared to that of the linear analogues. Consequently, the reduced lamellae tortuosity of self-assembled star BCPs improved the lithium conductivity by more than 8 times at 30 °C for ∼30 wt % of the POEGA conductive phase.

Live-Cell Imaging of the Assembly and Ejection Processes of the Bacterial Flagella by Fluorescence Microscopy.

Bacterial flagella are molecular machines used for motility and chemotaxis. The flagellum consists of a thin extracellular helical filament as a propeller, a short hook as a universal joint, and a basal body as a rotary motor. The filament is made up of more than 20,000 flagellin molecules and can grow to several micrometers long but only 20 nanometers thick. The regulation of flagellar assembly and ejection is important for bacterial environmental adaptation. However, due to the technical difficulty to observe these nanostructures in live cells, our understanding of the flagellar growth and loss is limited. In the last three decades, the development of fluorescence microscopy and fluorescence labeling of specific cellular structure has made it possible to perform the real-time observation of bacterial flagellar assembly and ejection processes. Furthermore, flagella are not only critical for bacterial motility but also important antigens stimulating host immune responses. The complete understanding of bacterial flagellar production and ejection is valuable for understanding macromolecular self-assembly, cell adaptation, and pathogen-host interactions.

Hierarchical Coarse-Grained Strategy for Macromolecular Self-Assembly: Application to Hepatitis B Virus-Like Particles.

Macromolecular self-assembly is at the basis of many phenomena in material and life sciences that find diverse applications in technology. One example is the formation of virus-like particles (VLPs) that act as stable empty capsids used for drug delivery or vaccine fabrication. Similarly to the capsid of a virus, VLPs are protein assemblies, but their structural formation, stability, and properties are not fully understood, especially as a function of the protein modifications. In this work, we present a data-driven modeling approach for capturing macromolecular self-assembly on scales beyond traditional molecular dynamics (MD), while preserving the chemical specificity. Each macromolecule is abstracted as an anisotropic object and high-dimensional models are formulated to describe interactions between molecules and with the solvent. For this, data-driven protein-protein interaction potentials are derived using a Kriging-based strategy, built on high-throughput MD simulations. Semi-automatic supervised learning is employed in a high performance computing environment and the resulting specialized force-fields enable a significant speed-up to the micrometer and millisecond scale, while maintaining high intermolecular detail. The reported generic framework is applied for the first time to capture the formation of hepatitis B VLPs from the smallest building unit, i.e., the dimer of the core protein HBcAg. Assembly pathways and kinetics are analyzed and compared to the available experimental observations. We demonstrate that VLP self-assembly phenomena and dependencies are now possible to be simulated. The method developed can be used for the parameterization of other macromolecules, enabling a molecular understanding of processes impossible to be attained with other theoretical models.

Stimuli-Responsive Macromolecular Self-Assembly

Macromolecular self-assembly has great potential for application in the field of the design of molecular machines, in molecular regulation, for biological tissue, and in biomedicine for the optical, electrical, and biological characteristics that the assembly unit does not possess. In this paper, the progress in macromolecular self-assembly is systematically reviewed, including its conception, processes and mechanisms, with a focus on macromolecular self-assembly by stimuli. According to the difference in stimuli, macromolecular self-assembly can be classified into temperature-responsive self-assembly, light-responsive self-assembly, pH-responsive self-assembly, redox-responsive self-assembly, and multi-responsive self-assembly. A preliminary study on constructing dynamic macromolecular self-assembly based on a chemical self-oscillating reaction is described. Furthermore, the problems of macromolecular self-assembly research, such as the extremely simple structure of artificial self-assembly and the low degree of overlap between macromolecular self-assembly and life sciences, are analyzed. The future development of stimuli-responsive macromolecular self-assembly should imitate the complex structures, processes and functions in nature and incorporate the chemical-oscillation reaction to realize dynamic self-assembly.

Boosting Organic Afterglow Performance via a Two-Component Design Strategy Extracted from Macromolecular Self-Assembly

Because intersystem crossing and phosphorescence decay are spin-forbidden in organic systems, it is challenging to obtain high-performance organic afterglow materials. Inspired by two-component design strategy from macromolecular self-assembly, here we report the utilization of synthetic polymers to control the excited state properties of difluoroboron β-diketonate (BF2bdk) and deuterated BF2bdk compounds for the fabrication of room-temperature organic afterglow materials. The polymer component can interact with BF2bdk excited states by dipole-dipole interactions, lower BF2bdk S1 levels with insignificant effect on T1 levels, reduce ΔEST, and thus enhance intersystem crossing of BF2bdk excited states. The polymer component can also suppress intramolecular motion of BF2bdk triplets and protect BF2bdk triplets from oxygen quenching. The obtained BF2bdk-polymer afterglow materials exhibit emission lifetimes up to 2.2 s and high photoluminescence quantum yields under ambient conditions, display excellent processability and flexibility, and can function as efficient donors for excited state energy transfer to construct red afterglow materials.

Tuning Supramolecular Polymers' Amphiphilicity via Host-Guest Interfacial Recognition for Stabilizing Multiple Pickering Emulsions.

Supramolecular host-guest chemistry bridging the adjustable amphiphilicity and macromolecular self-assembly is well advanced in aqueous media. However, the interfacial self-assembled behaviors have not been further exploited. Herein, we designed a β-cyclodextrin-grafted alginate/azobenzene-functionalized dodecyl (Alg-β-CD/AzoC12) supra-amphiphilic system that possessed tunable amphiphilicity by host-guest interfacial self-assembly. Especially, supra-amphiphilic aggregates could be utilized as highly efficient soft colloidal emulsifiers for stabilizing water-in-oil-water (W/O/W) Pickering emulsions due to the excellent interfacial activity. Meanwhile, the assembled particle structures could be modulated by adjusting the oil-water ratio, resulting from the tunable aggregation behavior of supra-amphiphilic macromolecules. Additionally, the interfacial adsorption films could be partially destroyed/reconstructed upon ultraviolet/visible irradiation due to the stimuli-altering balance of amphiphilicity of Alg-β-CD/AzoC12 polymers, further constructing the stimulus-responsive Pickering emulsions. Therefore, the supramolecular interfacial self-assembly-mediated approach not only technologically advances the continued development of creative templates to construct multifunctional soft materials with anisotropic structures but also serves as a creative bridge between supramolecular host-guest chemistry, colloidal interface science, and soft material technology.

Polymer cyclization for the emergence of hierarchical nanostructures

The creation of synthetic polymer nanoobjects with well-defined hierarchical structures is important for a wide range of applications such as nanomaterial synthesis, catalysis, and therapeutics. Inspired by the programmability and precise three-dimensional architectures of biomolecules, here we demonstrate the strategy of fabricating controlled hierarchical structures through self-assembly of folded synthetic polymers. Linear poly(2-hydroxyethyl methacrylate) of different lengths are folded into cyclic polymers and their self-assembly into hierarchical structures is elucidated by various experimental techniques and molecular dynamics simulations. Based on their structural similarity, macrocyclic brush polymers with amphiphilic block side chains are synthesized, which can self-assemble into wormlike and higher-ordered structures. Our work points out the vital role of polymer folding in macromolecular self-assembly and establishes a versatile approach for constructing biomimetic hierarchical assemblies.

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Construction of β-Cyclodextrin-phosphomolybdate grafted polypyrrole composite: Application as a disposable electrochemical sensor for detection of propylparaben

Herein, a newly introduced electrochemical sensor based on polypyrrole (PPy) grafted by the organic–inorganic β-Cyclodextrin (β-CD)-phosphomolybdate (PMo12) composite is reported for detection of propylparaben (PP). The host–guest chemistry was utilized to synthesize the macromolecular self-assembly of β-CD-PMo12 that was subsequently verified by nuclear magnetic resonance (NMR) spectroscopy and used as a kind of dopant for electropolymerization of pyrrole (Py) on a pencil graphite electrode (PGE). The morphology and the physical properties of the electrodeposited film were characterized using field emission scanning electron microscopy (FE-SEM), Fourier transform infrared (FT-IR) spectroscopy, electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV). Overoxidation of the electropolymerized film was necessary for conditioning the modified electrode to detect PP. Following the optimization of the important influential parameters on the sensor response towards PP, differential pulse voltammetry (DPV) was used to construct the concentration calibration curve. The designed sensor demonstrated two linear responses within the ranges of 0.2 µM to 10 µM and 10 µM to 100 µM with limits of detection (LOD) and quantification (LOQ) of 0.04 μM and 0.1 μM based on 3sb/m and 10sb/m criteria, respectively. The real analytical applicability of the proposed sensor was examined through the determination of PP in a commercial cleansing micellar solution, which showed acceptable recoveries and favorable performance.

Conformation-dependent sequence design of polymer chains in melts

Conformation-dependent design of polymer sequences can be considered as a tool to control macromolecular self-assembly. We consider the monomer unit sequences created via the modification of polymers in a homogeneous melt in accordance with the spatial positions of the monomer units. The geometrical patterns of lamellae, hexagonally packed cylinders, and balls arranged in a body-centered cubic lattice are considered as typical microphase-separated morphologies of block copolymers. Random trajectories of polymer chains are described by the diffusion-type equations and, in parallel, simulated in the computer modeling, the probability distributions of block length k being calculated. The problem is similar to that of gambler’s ruin and first passage time in probability theory but the consideration is generalized to 3D and the domains of different shapes are considered. In any domain, the probability distribution can be described by the asymptote ∼k −3/2 at moderate values of k if the spatial size of the block is less than the smallest characteristic size of the domain. For large blocks, the exponential asymptote exp(−const ) is valid, d as being the asymptotic domain length (a is the monomer unit size). The number average block lengths and their dispersities change linearly with the domain size for lamellae, cylinders, and balls, when the domain is characterized by a single characteristic size. If the domain is described by more than one size, the number average block length can grow nonlinearly with the domain sizes and the length d as can depend on all of them.

Recyclable DMAP-Functionalized polymeric nanoreactors for highly efficient acylation of alcohols in aqueous systems

Fabrication of highly efficient and recyclable nanoreactors via macromolecular self-assembly represents a promising strategy for green organic transformation. In this study, small-molecule catalysts 4-(N,N-dimethylamino)pyridine (DMAP) functionalized nanoreactors were constructed by self-assembly of amphiphilic block copolymers with DMAP moieties in the hydrophobic block, leading to heterogeneous catalysts with excellent dispersity in water. The key preparation route included reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(N-methyl-N-(4-pyridyl)amino)ethyl methacrylate (MAPMA) and methyl methacrylate (MMA) using poly (oligomeric (ethylene glycol) methyl ether methacrylate) (POEGMA) as a hydrophilic macromoleculer RAFT reagent. The characterization by dynamic light scattering (DLS) and transmission electron microscopy (TEM) shows that the nanoreactors possess a core-shell nanostructure with the diameter of around 110 nm. The resulting polymeric nanoreactors showed excellent catalytic activity for acylation of alcohols in water. High conversion of a variety of alcohol (>99%) and excellent product selectivity were achieved. The high catalytic efficiency of the nanoreactors may be attributed to the enhancement of the interaction between the reactant and the catalyst in the confined hydrophobic space, which simulates how enzymes usually work. Moreover, the catalyst could be easily recovered by thermos-responsive separation and reused with high activity for more than 5 cycles. This study presents an efficient approach to achieve green catalytic reactions which are normally incompatible to aqueous conditions, potentially applicable to other catalytic systems such as metal-mediated organic transformations.

Preparation of electroconductive film based on self-assembled aminothiophene/poly(γ-glutamate) nanoparticles and its application in biosensor

An electroconductive nanoparticles (NPs) film consisting of sodium poly(γ-glutamate) (γ-PGANa) and 3,4-diaminothiophene dihydrochloride (DATh) was simply prepared through macromolecular self-assembly and electropolymerization methods. Firstly, the γ-PGANa and the DATh underwent a complexation to form DATh/γ-PGANa composites through the electrostatic interaction; the DATh/γ-PGANa composites were then self-assembled into DATh/γ-PGANa NPs through decreasing the pH value in aqueous solution. Next, an electroconductive NPs film was formed on the surface of a gold electrode by casting the DATh/γ-PGANa NPs and subsequently electropolymerizing the DATh. Last, horseradish peroxidase and Nafion were cast onto the NPs film to obtain an enzymatic biosensor for H2O2 detection. The electroconductive DATh/γ-PGANa NPs film endowed the biosensor with high sensitivity. Under the optimal conditions, the prepared biosensor showed a linear range from 1 × 10−11 to 1 × 10−4 mol·L−1 with a detection limit of 3 × 10−12 mol·L−1 for H2O2 detection. The biosensor can retain its detection performance for 4 weeks. The response currents of the biosensor changed little after adding the interferent into the analyte. The standard deviation of the response between different biosensors did not exceed 2.5%.

Poly(2-oxazoline)- and Poly(2-oxazine)-Based Self-Assemblies, Polyplexes, and Drug Nanoformulations-An Update.

For many decades, poly(2-oxazoline)s and poly(2-oxazine)s, two closely related families of polymers, have led the life of a rather obscure research topic with only a few research groups world-wide working with them. This has changed in the last five to ten years, presumably triggered significantly by very promising clinical trials of the first poly(2-oxazoline)-based drug conjugate. The huge chemical and structural toolbox poly(2-oxazoline)s and poly(2-oxazine)s has been extended very significantly in the last few years, but their potential still remains largely untapped. Here, specifically, the developments in macromolecular self-assemblies and non-covalent drug delivery systems such as polyplexes and drug nanoformulations based on poly(2-oxazoline)s and poly(2-oxazine)s are reviewed. This highly dynamic field benefits particularly from the extensive synthetic toolbox poly(2-oxazoline)s and poly(2-oxazine)s offer and also may have the largest potential for a further development. It is expected that the research dynamics will remain high in the next few years, particularly as more about the safety and therapeutic potential of poly(2-oxazoline)s and poly(2-oxazine)s is learned.

(Macro)molecular self-assembly for hydrogel drug delivery.

Hydrogels prepared via self-assembly offer scalable and tunable platforms for drug delivery applications. Molecular-scale self-assembly leverages an interplay of attractive and repulsive forces; drugs and other active molecules can be incorporated into such materials by partitioning in hydrophobic domains, affinity-mediated binding, or covalent integration. Peptides have been widely used as building blocks for self-assembly due to facile synthesis, ease of modification with bioactive molecules, and precise molecular-scale control over material properties through tunable interactions. Additional opportunities are manifest in stimuli-responsive self-assembly for more precise drug action. Hydrogels can likewise be fabricated from macromolecular self-assembly, with both synthetic polymers and biopolymers used to prepare materials with controlled mechanical properties and tunable drug release. These include clinical approaches for solubilization and delivery of hydrophobic drugs. To further enhance mechanical properties of hydrogels prepared through self-assembly, recent work has integrated self-assembly motifs with polymeric networks. For example, double-network hydrogels capture the beneficial properties of both self-assembled and covalent networks. The expanding ability to fabricate complex and precise materials, coupled with an improved understanding of biology, will lead to new classes of hydrogels specifically tailored for drug delivery applications.

Reaction-induced phase transitions with block copolymers in solution and bulk

Reaction-induced phase transitions use chemical reactions to drive macromolecular organisation and self-assembly. This review highlights significant and recent advancements in this burgeoning field.