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peer-reviewed Molecular stacking modes, generally classified as H-, J-, and X-aggregation, play a key role in determining the optoelectronic properties of organic crystals. However, the control of stacking transformation of a specific molecule is an unmet challenge, and a priori prediction of the performance in different stacking modes is extraordinarily difficult to achieve. In particular, the existence of hybrid stacking modes and their combined effect on physicochemical properties of molecular crystals are not fully understood. Herein, unexpected stacking transformation from H- to J- and X-aggregation is observed in the crystal structure of a small heterocyclic molecule, 4,4'-bipyridine (4,4'-Bpy), upon coassembly with N-acetyl-l-alanine (AcA), a nonaromatic amino acid derivative. This structural transformation into hybrid stacking mode improves physicochemical properties of the cocrystals, including a large red-shifted emission, enhanced supramolecular chirality, improved thermal stability, and higher mechanical properties. While a single crystal of 4,4'-Bpy shows good optical waveguiding and piezoelectric properties due to the uniform elongated needles and low symmetry of crystal packing, the significantly lower band gap and resistance of the cocrystal indicate improved conductivity. This study not only demonstrates cocrystallization-induced packing transformation between H-, J-, and X-aggregations in the solid state, leading to tunable mechanical and optoelectronic properties, but also will inspire future molecular design of organic functional materials by the coassembly strategy. ACCEPTED peer-reviewed

Hierarchical self-assembly and crystallization with long-range ordered spatial arrangement is ubiquitous in nature and plays an essential role in the regulation of structures and biological functions. Inspired by the multiscale hierarchical structures in biology, tremendous efforts have been devoted to the understanding of hierarchical self-assembly and crystallization of biomolecules such as peptides and amino acids. Understanding the fundamental mechanisms underlying the construction and organization of multiscale architectures is crucial for the design and fabrication of complex functional systems with long-range alignment of molecules. This Review summarizes the typical examples for hierarchically oriented organization of peptide self-assembly and discusses the thermodynamic and kinetic mechanisms that are responsible for this specific hierarchical organization. Most importantly, we propose the concept of hierarchically oriented organization for self-assembling peptide crystals, distinct from the traditional growth mechanism of supramolecular polymerization and crystallization based on the Ostwald ripening rule. Finally, we assess critical challenges and highlight future directions towards the mechanistic understanding and versatile application of the hierarchically oriented organization mechanism. Hierarchical self-assembly and crystallization is ubiquitous in nature and is of key importance for creation of complex superstructures. Herein, Yuan and co-workers propose that hierarchically oriented organization guides the formation of such complex systems, especially in supramolecular peptide crystals.

Peptide-based supramolecular hydrogels as functional soft materials hold great promising for biomedical applications. However, much effort has been devoted to the finding and development of linear peptide hydrogelators and related hydrogel materials. Usually, linear peptide hydrogels are subject to the environmental variations and suffer from rapid enzymatic degradation in physiological conditions, limiting their more broad range of applications. Herein, we discover that a cyclic dipeptide (Cyclo-(Leu-Phe), CLF) can serve as a versatile hydrogelator for formation of supramolecular hydrogels at various physiological and harsh environments including the presence of salts, proteins and enzymes as well as acidic and basic aqueous solutions. Importantly, the CLF hydrogels show robust stability and excellent rheological properties at the various conditions, which are attributable to the rigid molecular structure of cyclic dipeptides and their strong 3-dimentional intermolecular hydrogen bonding networks. Hence, cyclic dipeptides provide a new alternative for development of peptide-based hydrogel materials with properties and functions more adapted for the complex and harsh environments.

The misfolding of proteins and peptides potentially leads to a conformation transition from an α-helix or random coil to β-sheet-rich fibril structures, which are associated with various amyloid degenerative disorders. Inhibition of the β-sheet aggregate formation and control of the structural transition could therefore attenuate the development of amyloid-associated diseases. However, the structural transitions of proteins and peptides are extraordinarily complex processes that are still not fully understood and thus challenging to manipulate. To simplify this complexity, herein, the effect of metal ions on the inhibition of amyloid-like β-sheet dipeptide self-assembly is investigated. By changing the type and ratio of the metal ion/dipeptide mixture, structural transformation is achieved from a β-sheet to a superhelix or random coil, as confirmed by experimental results and computational studies. Furthermore, the obtained supramolecular metallogel exhibits excellent in vitro DNA binding and diffusion capability due to the positive charge of the metal/dipeptide complex. This work may facilitate the understanding of the role of metal ions in inhibiting amyloid formation and broaden the future applications of supramolecular metallogels in three-dimensional (3D) DNA biochip, cell culture, and drug delivery.

Clinical translation of curcumin has been highly obstructed by the rapid degradation and poor tissue absorption of this agent. Herein, we report on the generation of supramolecular curcumin nanoagents through amino acid coordination driven self-assembly to simultaneously increase the biological stability and tumor accumulation of curcumin. The biological stability of curcumin was significantly improved both through coordination and through molecular stacking. The sizes of these nanoagents can be readily manipulated to facilitate tumor accumulation. These favorable therapeutic features, together with high drug-loading capacities and responses to pH and redox stimuli, substantially enhanced the antitumor activity of curcumin without discernible side effects. Hence, supramolecular curcumin nanoagents may hold promise in moving forward the clinical application of curcumin as an effective anticancer drug.

Utilizing customized deep-ultraviolet laser ionization mass spectroscopy, here we report a finding of remarkable dehydrogenation product of N,N-dimethyl-p-toluidine (DMT). The DMT dehydrogenates find comparable mass abundance with the DMT molecule ions showing decent stability at the loss of one electron and one H atom from the DMT molecule. First-principles calculation reveals that the dehydrogenation most readily occurs at the N-connected methyl group. Furthermore, at the removal of a hydrogen atom, a neighboring hydrogen atom on the other methyl come close and interact with the dehydrogenated methylene group, pertaining to C-H···C weak interactions which give rises to a resonant structure (C···H-C) on a basis of hydrogen atom quantum tunneling effect. The quantum tunneling tautomer of DMT dehydrogenates displays reversible donor-acceptor charge-transfer interactions as demonstrated by natural bonding orbital analysis and vibrational spectroscopy. It is worth noting that the novel dehydrogenation product was also observed for another small organic molecule o-phenylenediamine, which bears two neighboring amino groups and the subsequent dehydrogenation product pertains to resonant structures of N-H···N and N···H-N. The deep ultraviolet laser not only produces fragmentation-free mass spectra for such small organic molecules but also tailors the interesting quantum tunneling tautomer from such specific molecules.

The application of low-fragmentation mass spectrometry to identify chemicals has been recognized to be of particular importance in chemistry, biomedicine, and materials science. Utilizing a customized all-solid-state picosecond-pulsed deep-ultraviolet (DUV) laser, here we present new advances into photoionization mass spectrometry. The DUV laser ionization mass spectrometry (DUV-LIMS) results in very clean spectra pertaining to minimized structure relaxation and fragmentation under the ultrafast ionization process. Typical DUV-LIMS applications are illustrated not only for small organic molecules but also for long-chain unsaturated hydrocarbons and clusters of benzene. The unique advantages of DUV-LIMS enable us to detect and analyze confusing organic compound mixtures, indicating promising applications. DUV-LIMS is also found to be applicable in the identification of phenylenediamine isomers. An in-depth analysis of reaction dynamics is provided showing how hydrogen-atom-transfer (HAT) initiates the distinguishable photodissociation of phenylenediamines under near-resonant excitation. In particular, ortho-phenylenediamine (OPD) finds a remarkable dehydrogenation product with comparable intensity to the molecular ion peak, which is associated with the quantum tunnelling tautomers, providing new subjects for studying intramolecular noncovalent interactions.

Secondary structures such as α-helix and β-sheet are the major structural motifs within the three-dimensional geometry of proteins. Therefore, structure transitions from β-sheet to α-helix not only can serve as an effective strategy for the therapy of neurological diseases through the inhibition of β-sheet aggregation but also extend the application of α-helix fibrils in biomedicine. Herein, we present a charge-induced secondary structure transition of amyloid-derived dipeptide assemblies from β-sheet to α-helix. We unravel that the electrostatic (charge) repulsion between the C-terminal charges of the dipeptide molecules are responsible for the conversion of the secondary structure. This finding provides a new perspective to understanding the secondary structure formation and transformation in the supramolecular organization and life activity.

Controlled phase transformation involving biomolecular organization to generate dynamic biomimetic self-assembly systems and functional materials is currently an appealing topic of research on molecular materials. Herein, we achieve by ultrasonic irradiation the direct solid-solid transition of bioinspired dipeptide organization from triclinic structured aggregates to nanofibers and eventually to monoclinic nanobelts with strong polarized luminescence. It is suggested that the locally high temperature and pressure produced by cavitation effects cleaves the hydrophobic, π-π stacking or self-locked intramolecular interactions involved in one phase state and then rearranges the molecular packing to form another well-ordered aromatic dipeptide crystalline structure. Such a sonication-modulated solid-solid phase transition evolution is governed by distinct molecular interactions at different stages of structural organization. The resulting crystalline nanobelts are for the first time applied for polarization imaging of cells, which can be advantageous to directly inspect the uptake and fate of nanoscale delivery platforms without labeling of fluorescent dyes. This finding provides a new perspective to comprehend the dynamic evolution of biomolecular self-organization with energy supply by an external field and open up a facile and versatile approach of using anisotropic nanostructures for polarization imaging of cells and even live organisms in future.

Prototypes of biosystems provide good blueprints for the design and creation of biomimetic systems. However, mimicking both the sophisticated natural structures and their complex biological functions still remains a great challenge. Herein, chloroplast mimics have been fabricated by one-step bioinspired amino acid mineralization and simultaneous integration of catalytically active units. Hierarchically structured crystals were obtained by the metal-ion-directed self-assembly of cystine (the oxidized dimer of the amino acid cysteine), with a porous structure and stacks of nanorods, which show similar architectural principles to chloroplasts. Porphyrins and enzymes can both be encapsulated inside the crystal during mineralization, rendering the crystal photocatalytically and enzymatically active for an efficient and sustainable synthesis of hydrogen and acetaldehyde in a coupled photoenzymatic reaction.

Conformational transition of proteins and peptides into highly stable, β-sheet-rich structures is observed in many amyloid-associated neurodegenerative disorders, yet the precise mechanism of amyloid formation at the molecular level remains poorly understood due to the complex molecular structures. Short peptides provide simplified models for studying the molecular basis of the assembly mechanism that governs β-sheet fibrillation processes underlying the formation and inhibition of amyloid-like structures. Herein, we report a supramolecular coassembly strategy for the inhibition and transformation of stable β-sheet-rich amyloid-derived dipeptide self-assemblies into adaptable secondary structural fibrillar assemblies by mixing with bipyridine derivatives. The interplay between the type and mixing ratio of bipyridine derivatives allowed the variable coassembly process with stimuli-responsive functional properties, studied by various experimental characterizations and computational methods. Furthermore, the resulting coassemblies showed functional redox- and photoresponsive properties, making them promising candidates for controllable drug release and fluorescent imprint. This work presents a coassembly strategy not only to explore the mechanism of amyloid-like structure formation and inhibition at the molecular level but also to manipulate amyloid-like structures into responsive supramolecular coassemblies for material science and biotechnology applications.

There is a real need for new antibiotics against self-evolving bacteria. One option is to use biofriendly broad-spectrum and mechanically tunable antimicrobial hydrogels that can combat multidrug-resistant microbes. Whilst appealing, there are currently limited options. Herein, broad-spectrum antimicrobial biometallohydrogels based on the self-assembly and local mineralization of Ag+ -coordinated Fmoc-amino acids are reported. Such biometallohydrogels have the advantages of localized delivery and sustained release, reduced drug dosage and toxicity yet improved bioavailability, prolonged drug effect, and tunable mechanical strength. Furthermore, they can directly interact with the cell walls and membrane, resulting in the detachment of the plasma membrane and leakage of the cytoplasm. This leads to cell death, triggering a significant antibacterial effect against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria in cells and mice. This study paves the way for developing a multifunctional integration platform based on simple biomolecules coordinated self-assembly toward a broad range of biomedical applications.

Supramolecular peptide materials have attracted increasing attention due to their natural biological origin and versatile applications. However, it is often challenging to control and modulate the self-assembly of peptides (especially short peptides) for constructing hydrogels with tunable mechanical properties and adaptive injectability toward biomedical applications. Here, we report a supramolecular strategy for forming robust and injectable hydrogels based on the self-assembly of a rationally designed bola-dipeptide. The self-assembled hydrogels exhibit versatile functionalities, including flow under shear stress, good recovery properties, and easy encapsulation of hydrophilic prodrugs. The prodrug-loaded hydrogels show sustained release profiles, inhibited nontargeted leakage, and enhanced localized prodrug conversion, leading to highly efficient photodynamic tumor ablation. Hence, the supramolecular strategy is promising for the rational construction of injectable hydrogels toward targeted and sustained prodrug conversion and tumor therapy.

Cyclic dipeptides (CDPs), the smallest naturally occurring cyclic peptides, have attracted tremendous attention due to their exceptional biological and pharmacological activities such as antitumor, antimicrobial, and immune regulation. However, controlled fabrication of CDPs nanostructures to address the problem of poor aqueous solubility and low bioavailability existing in therapeutic application is still in challenging, due to their remarkable structural rigidity and superior hydrogen-bonding-forming capability. Herein, a simple but robust and universal strategy for the construction of CDP nanoribbons based on the amphiphilic dye-mediated hydrophobic self-assembly is presented. The amphiphilic dyes not only provide the robust hydrophobic interaction for the formation of CDP nanoribbons but also offer enough electrostatic repulsion forces to stabilize the formed assemblies. Moreover, the introduction of functional dyes endows the assembled CDP nanoribbons multiple benign therapeutic features, including adjustable shape and size, improved bioavailability, as well as preferable cellular uptake and biodistribution, thereby enhanced chemotherapy efficacy in vitro and in vivo. The strategy developed based on the dye-mediated self-assembly provides a promising way to rationally design water-insoluble bioactive CDPs for therapeutic applications.

Cluster assembly materials with unique electronic and optical properties are significant for a variety of potential applications but often susceptible to intermolecular interactions which may alter the performance determined by their individual components. For the first time, here we report the assembly of a pyridine-protected tungsten–copper cluster on porous alumina, and find superior optical limiting (OL) properties retainable for multilevel clustering due to unaffected reverse saturable absorption (RSA) and constant photo-excited triplet states. Also clarified is that this transition metal W–Cu cluster bears an interesting framework structure with reasonable stability reinforced by strong donor–acceptor charge-transfer interactions.

Understanding the influence of the molecular architecture on the self-assembly and properties of supramolecular organogel materials is necessary for elucidating the structure-property relationship. Although conventional gelation motifs (e.g., amides, long alkyl side chains, and steroidal groups) have been considered essential for the effective gel process, the lack of gelation motifs hinders the development and self-assembly of non-conventional gelators. Herein, coumarin-based derivatives (1–12) without a conventional gelation motif were designed and synthesised by inducing a one-step reaction that entails fine-tuning the molecular architecture, particularly the position of the nitrogen atom in pyridine, the substitution position of pyridine, and the placement of methyl in coumarin. A previous gelation study revealed that 7-substituted coumarin-based derivatives with methyl (1–4) are highly efficient gelators that can self-assemble to form different nanostructures, and gelate various polar protic solvents. After small-scale modification of the molecular structures, Derivatives 5–6 self-assembled and only formed gels in the alcohol phase, whereas gels were not formed by Derivatives 7–12 in various solvents. Interestingly, the fluorescence property of these gels was significantly influenced by the dielectric constant and viscosity of the solvent. Furthermore, differences in the self-assembly and fluorescence of gelators were numerically investigated by performing density functional theory calculations and all-atom molecular dynamics simulations. This study provides a foundation for the development of a low-cost, non-conventional supramolecular organogel system with minimal building blocks, a modifiable self-assembly pathway, and alterable properties.

Photothermal nanomaterials that integrate multimodal imaging and therapeutic functions provide promising opportunities for noninvasive and targeted diagnosis and treatment in precision medicine. However, the clinical translation of existing photothermal nanoagents is severely hindered by their unclear physiological metabolism, which makes them a strong concern for biosafety. Here, the utilization of biliverdin (BV), an endogenic near-infrared (NIR)-absorbing pigment with well-studied metabolic pathways, to develop photothermal nanoagents with the aim of providing efficient and metabolizable candidates for tumor diagnosis and therapy, is demonstrated. It is shown that BV nanoagents with intense NIR absorption, long-term photostability and colloidal stability, and high photothermal conversion efficiency can be readily constructed by the supramolecular multicomponent self-assembly of BV, metal-binding short peptides, and metal ions through the reciprocity and synergy of coordination and multiple noncovalent interactions. In vivo data reveal that the BV nanoagents selectively accumulate in tumors, locally elevate tumor temperature under mild NIR irradiation, and consequently induce efficient photothermal tumor ablation with promising biocompatibility. Furthermore, the BV nanoagents can serve as a multimodal contrast for tumor visualization through both photoacoustic and magnetic resonance imaging. BV has no biosafety concerns, and thereby offers a great potential in precision medicine by integrating multiple theranostic functions.

Supramolecular photosensitizer nanodrugs that combine the flexibility of supramolecular self-assembly and the advantage of spatiotemporal, controlled drug delivery are promising for dedicated, precise, noninvasive tumor therapy. However, integrating robust blood circulation and targeted burst release in a single photosensitizer nanodrug platform that can simultaneously improve the therapeutic performance and reduce side effects is challenging. Herein, we demonstrate a multicomponent coordination self-assembly strategy that is versatile and potent for the development of photodynamic nanodrugs. Inspired by the multicomponent self-organization of polypeptides, pigments, and metal ions in metalloproteins, smart metallo-nanodrugs are constructed based on the combination and cooperation of multiple coordination, hydrophobic, and electrostatic noncovalent interactions among short peptides, photosensitizers, and metal ions. The resulting metallo-nanodrugs have uniform sizes, well-defined nanosphere structures, and high loading capacities. Most importantly, multicomponent assembled nanodrugs have robust colloidal stability and ultrasensitive responses to pH and redox stimuli. These properties prolong blood circulation, increase tumor accumulation, and enhance the photodynamic tumor therapeutic efficacy. This study offers a new strategy to harness robust, smart metallo-nanodrugs with integrated flexibility and multifunction to enhance tumor-specific delivery and therapeutic effects, highlighting opportunities to develop next-generation, smart photosensitizing nanomedicines.

The interaction between water and biomolecules including peptides is of critical importance for forming high-level architectures and triggering life's functions. However, the bulk aqueous environment has limitations in detecting the kinetics and mechanisms of peptide self-assembly, especially relating to interactions of trace water. With ionic liquids (ILs) as a nonconventional medium, herein, it is discovered that trace amounts of water play a decisive role in triggering self-assembly of a biologically derived dipeptide. ILs provide a suitable nonaqueous environment, enabling us to mediate water content and follow the dynamic evolution of peptide self-assembly. The trace water is found to be involved in the assembly process of dipeptide, especially leading to the formation of stable noncovalent dipeptide oligomers in the early stage of nucleation, as evident by both experimental studies and theoretical simulations. The thermodynamics of the growth process is mainly governed by a synergistic effect of hydrophobic interaction and hydrogen bonds. Each step of assembly presents a different trend in thermodynamic energy. The dynamic evolution of assembly process can be efficiently mediated by changing trace water content. The decisive role of trace water in triggering and mediating self-assembly of biomolecules provides a new perspective in understanding supramolecular chemistry and molecular self-organization in biology.

Hierarchical self-assembly, abundant in biological systems, has been explored as an effective bottom-up method to fabricate highly ordered functional superstructures from elemental building units. Biomolecules, especially short peptides consisting of several amino acids, are a type of elegant building blocks due to their advantages of structural, mechanical, and functional diversity as well as high biocompatibility and biodegradability. The hierarchical self-assembly of peptides is a spontaneous process spanning multiple time and length scales under certain thermodynamics and kinetics conditions. Therefore, understanding the mechanisms of dynamic processes is crucial to directing the construction of complicated biomimetic systems with multiple functionalities. Multiscale molecular simulations that combine and systematically link several hierarchies can provide insights into the evolution and dynamics of hierarchical self-assembly from the molecular level to the mesoscale. Herein, we provided an overview of the simulation hierarchies in the general field of peptide self-assembly modeling. In particular, we highlighted multiscale simulations for unraveling the mechanisms underlying the dynamic self-assembly process with an emphasis on weak intermolecular interactions in the process stages and the energies of different molecular alignments as well as the role of thermodynamic and kinetic factors at the microscopic level.

We report here the development of a reflectron time-of-flight mass spectrometer utilizing single-photon ionization based on an all-solid-state deep ultraviolet (DUV) laser system. The DUV laser was achieved from the second harmonic generation using a novel nonlinear optical crystal KBe2BO3F2 under the condition of high-purity N2 purging. The unique property of this laser system (177.3-nm wavelength, 15.5-ps pulse duration, and small pulse energy at ∼15 μJ) bears a transient low power density but a high single-photon energy up to 7 eV, allowing for ionization of chemicals, especially organic compounds free of fragmentation. Taking this advantage, we have designed both pulsed nanospray and thermal evaporation sources to form supersonic expansion molecular beams for DUV single-photon ionization mass spectrometry (DUV-SPI-MS). Several aromatic amine compounds have been tested revealing the fragmentation-free performance of the DUV-SPI-MS instrument, enabling applications to identify chemicals from an unknown mixture.

Interactions between tetracyanoquinodimethane (TCNQ) and two typical silver clusters Ag13 and Ag20 are studied by first-principles DFT calculations. Charge transfer (CT) from silver clusters to TCNQ molecules initiates the Ag-N bond formation at selective sites resulting in the formation of different isomers of Ag13-TCNQ and Ag20-TCNQ complexes. We show here a comprehensive spectroscopic analysis for the two CT complexes on the basis of Raman and infrared activities. Furthermore, frontier molecular orbital (FMO) and natural bond orbital (NBO) analysis of the complexes provides a vivid illustration of electron cloud overlap and interactions. The behavior of TCNQ adsorbed on the tetrahedral Ag20 cluster was even found in good agreement with the experimental measurement of TCNQ molecules on a single-crystal Ag(111) surface. This study not only endeavors to clarify the charge-transfer interactions of TCNQ with silver, but also presents a finding of enhanced charge transfer between Ag13 and TCNQ indicating potential for candidate building blocks of granular materials.

Conformational transitions of secondary structures are a crucial factor in many protein misfolding diseases. However, the actual transition of folded proteins into β-sheet-rich structures is not fully understood. Inhibition of aggregate formation, mediated by the β-sheet conformation, and control of the secondary structural transition of proteins and peptides could potentially attenuate the development of amyloid-associated diseases. Here we describe a stoichiometry-controlled secondary structure transition of amyloid-derived dipeptide assemblies from a β-sheet to supramolecular helix conformation through co-assembly with a bipyridine derivative. The transition is mainly mediated by the intermolecular hydrogen bonds and π-π interactions between the two components, which induce the altered stacking and conformation of the co-assemblies, as confirmed by experimental results and computational simulations. This work not only exemplifies a feasible strategy to disrupt the β-sheet conformation, underlying amyloid-like fibril formation, but also provides a conceptual basis for the future utilization of the helical nanostructures in various biological applications. Bipyridine derivatives have been shown to control the self-assembly of amyloid-derived dipeptides. Here the authors show that 4,4'-bipyridine inhibits the formation of amyloid-like beta-sheet assembly by Fmoc-protected diphenylalanine, prompting a reorganisation to helical structure, and characterise the transition pathway.