Dynamic Intermolecular Interactions Research Articles

Biomolecular Condensates Based on Amino Acid for Enhancing Oral Bioavailability and Therapeutic Efficacy of Hydrophobic Drugs.

The oral administration of chemo- or immunotherapeutic drugs presents a compelling alternative for patients with malignant colorectal cancer, offering a convenient and patient-compliant "hospital-free" strategy. Unfortunately, the hydrophobic nature of many drug candidates, alongside the harsh conditions of the gastrointestinal tract, frequently results in suboptimal bioavailability and heightened systemic toxicity. To address these challenges, we harnessed the unique properties of biomolecular condensates, which form through a liquid-liquid phase separation mechanism, to develop a versatile platform for drug encapsulation and delivery. In this study, we introduce a reliable and effective amorphous oral drug delivery system based on biomolecular condensates derived from the amino acid derivative N-(benzyloxycarbonyl)-l-proline (ZP). These ZP condensates exhibit dynamic intermolecular interactions and possess unique physicochemical attributes such as fluidity and viscoelasticity. They significantly improve the solubility of hydrophobic drugs, ensuring enhanced stability and optimized pharmacokinetics under physiological and gastrointestinal conditions. By maintaining drugs in an amorphous state, we substantially increased drug bioavailability and markedly improved pharmacokinetics. Furthermore, the ZP condensates demonstrate potential as an integrated therapeutic platform capable of potentiating the synergies between chemotherapy and immunotherapy while concurrently reducing systemic toxicity. This has resulted in a significant enhancement of chemo-immunotherapy efficacy in the treatment of colorectal cancer, representing a notable advancement in drug delivery and oncology.

17O Solid-State NMR Spectroscopy of Lipid Membranes.

Despite the limitations posed by poor sensitivity, studies have reported the unique advantages of 17O based NMR spectroscopy to study systems existing in liquid, solid, or semisolid states. 17O NMR studies have exploited the remarkable sensitivity of quadrupole coupling and chemical shift anisotropy tensors to the local environment in the characterization of a variety of intra- and intermolecular interactions and motion. Recent studies have considerably expanded the use of 17O NMR to study dynamic intermolecular interactions associated with some of the challenging biological systems under magic angle spinning (MAS) and aligned conditions. The very fast relaxing nature of 17O has been well utilized in cellular and in vivo MRS (magnetic resonance spectroscopy) and MRI (magnetic resonance imaging) applications. The main focus of this Review is to highlight the new developments in the biological solids with a detailed discussion for a few selected examples including membrane proteins and nanodiscs. In addition to the unique benefits and limitations, the remaining challenges to overcome, and the impacts of higher magnetic fields and sensitivity enhancement techniques are discussed.

Theoretical studies on dynamic properties and intermolecular interactions of 2,4-dinitroimidazole crystals with different impurity defects

The density functional tight binding method and DFTB-based molecular dynamics simulations were used to study the intermolecular interactions and dynamic properties of 2,4-dinitroimidazole crystals doped with different amounts of 1,4-dinitroimidazole at different temperatures.

Comparative analysis of dielectric spectra in protic ionic liquids: Experimental findings and computational molecular decomposition

Using a combination of experimental measurements and polarizable molecular dynamics simulations, we investigate the dielectric spectra of the protic ionic liquid 1-methylimidazolium acetate, shedding light on their dynamic behavior and intermolecular interactions when adding 1-methylimidazolium trifluoroacetate to increase the fraction of a strong Brønsted acid in the system. The comparison between experimental and computational results provides valuable insights into the accuracy of the simulation models (with and without explicit proton transfer) and the ability to capture the intricate dynamical features of the protic ionic liquid. The investigation revealed complete deprotonation of trifluoroacetate, inducing a shift in the ionic liquid towards a more pronounced ionic state. The computational decomposition of the dielectric spectra into molecular translational and rotational contributions unveiled a reduction in the dielectric constant. This reduction was primarily ascribed to a decrease in translational contributions. Additionally, a strong correlation of the mutual orientation of molecules was found. The observed rise in conductivity upon the addition of 1-methylimidazolium trifluoroacetate to the system was attributed to an increase in proton transport.

Fighting Antimicrobial Resistance: Insights on How the Staphylococcus aureus NorA Efflux Pump Recognizes 2-Phenylquinoline Inhibitors by Supervised Molecular Dynamics (SuMD) and Molecular Docking Simulations.

The superbug Staphylococcus aureus (S. aureus) exhibits several resistance mechanisms, including efflux pumps, that strongly contribute to antimicrobial resistance. In particular, the NorA efflux pump activity is associated with S. aureus resistance to fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusion from cells. Thus, since efflux pump inhibitors (EPIs) are able to increase antibiotic concentrations in bacteria as well as restore their susceptibility to these agents, they represent a promising strategy to counteract bacterial resistance. Additionally, the very recent release of two NorA efflux pump cryo-electron microscopy (cryo-EM) structures in complex with synthetic antigen-binding fragments (Fabs) represents a real breakthrough in the study of S. aureus antibiotic resistance. In this scenario, supervised molecular dynamics (SuMD) and molecular docking experiments were combined to investigate for the first time the molecular mechanisms driving the interaction between NorA and efflux pump inhibitors (EPIs), with the ultimate goal of elucidating how the NorA efflux pump recognizes its inhibitors. The findings provide insights into the dynamic NorA-EPI intermolecular interactions and lay the groundwork for future drug discovery efforts aimed at the identification of novel molecules to fight antimicrobial resistance.

Spatiotemporally Responsive Hydrogel Dressing with Self-Adaptive Antibacterial Activity and Cell Compatibility for Wound Sealing and Healing.

Adhesive hydrogels containing quaternary ammonium salt (QAS) moieties have shown attractive advantages in treatment for acute wounds, attributed to their high performances in wound sealing and sterilization. However, the introduction of QAS commonly leads to high cytotoxicity and adhesive deterioration. Herein, aimed to solve these two issues, a self-adaptive dressing with delicate spatiotemporal responsiveness is developed by employing cellulose sulfate (CS) as dynamic layers to coat QAS-based hydrogel. In detail, due to the acid environment of wound in the early stages of healing, the CS coating will quickly detach to expose the active QAS groups for maximum disinfectant efficacy; meanwhile, as the wound gradually heals and recovers to a neutral pH, the CS will remain stable to keep QAS screened, realizing a high cell growth-promoting activity for epithelium regeneration. Additionally, attributed to the synergy of temporary hydrophobicity by CS and slow water absorption kinetics of the hydrogel, the resultant dressing possesses outstanding wound sealing and hemostasis performance. At last, this work anticipates this approach to intelligent wound dressings based on dynamic and responsive intermolecular interaction can also be applied to a wide range of self-adaptive biomedical materials employing different chemistries for applications in medical therapy and health monitoring.

A Smart Benzothiazole-Based Conjugated Polymer Nanoplatform with Multistimuli Response for Enhanced Synergistic Chemo-Photothermal Cancer Therapy

The combination of chemotherapy and phototherapy has received tremendous attention in multimodal cancer therapy. However, satisfactory therapeutic outcomes of chemo-photothermal therapy (chemo-PTT) still remain challenging. Herein, a biocompatible smart nanoplatform based on benzothiazole-linked conjugated polymer nanoparticles (CPNs) is rationally designed, for effectively loading doxorubicin (DOX) and Mo-based polyoxometalate (POM) through both dynamic chemical bond and intermolecular interactions, with an expectation to obtain new anticancer drugs with multiple stimulated responses to the tumor microenvironment (TME) and external laser irradiation. Controlled drug release of DOX from the obtained nanoformulation (CPNs-DOX-PEG-cRGD-BSA@POM) triggered by both endogenous stimulations (GSH and low pH) and exogenous laser irradiation has been well demonstrated by pharmacodynamics investigations. More intriguingly, incorporating POM into the nanoplatform not only enables the nanomedicine to achieve mild hyperthermia but also makes it exhibit self-assembly behavior in acidic TME, producing enhanced tumor retention. Benefiting from the versatile functions, the prepared CPNs-DOX-PEG-cRGD-BSA@POM exhibited excellent tumor targeting and therapeutic effects in murine xenografted models, showing great potential in practical cancer therapy.

Conjoined and non-conjoined coordination cages with palladium(II) vertices: structural diversity, solution dynamics, and intermolecular interactions.

Self-assembled coordination complexes prepared from a combination of Pd(II) components with one or more types of high-symmetry or low-symmetry bis/tris/tetrakis-monodentate ligands are considered in this review. The structures of these complexes are viewed in terms of the presence of a metallo-macromonocycle or conjoined metallo-macromonocycles/metallocages in the frameworks. Analysis of the typical molecular structures revealed an open truth that one or more units of metallo-macromonocycles can be conjoined to afford planar or non-planar systems. In the same line, the enveloping surface of a 3D cage can be considered as a multiple number of conjoined metallomacrocycles that embrace a 3D space from all directions. However, two or more units of cages are conjoined in a multi-3D-cavity cage system and such a system is considered as a conjoined cage. Construction of such conjoined cages having a finite but multiple number of 3D-cavities unified in a single molecular architecture is a challenging task when compared to that of single-3D-cavity based compounds. Conjoining of as many as four units of 3D cages is known so far. Single- as well as multi-cavity cages of lower symmetry have become a very recent trend in this regard where low-symmetry ligands or mixed ligand ensembles are crafted in the framework of the cages. Other structural diversities like helicity in cages, and supramolecular isomerism are also included in this assorted literature work. Although isomerism in classical coordination complexes is well known, it is very less studied in self-assembled coordination complexes. Ligand isomerism is one such feature that is reviewed here. The dynamic behavior of the cages results in interesting reactivity aspects. A large variety of dynamic processes are collected under an umbrella, i.e., "ligand exchange reactions" and described with examples. Intermolecular interaction among the already self-assembled molecules is possible in solution, solid, and gel-phases as discussed in the last part of this review. The understanding of intermolecular interaction is likely to influence different areas of research including crystal engineering, and materials chemistry.

Multiple yet switchable hydrogen-bonded organic frameworks with white-light emission

The development of new strategies to construct on-demand porous lattice frameworks from simple motifs is desirable. However, mitigating complexity while combing multiplicity and reversibility in the porous architectures is a challenging task. Herein, based on the synergy of dynamic intermolecular interactions and flexible molecular conformation of a simple cyano-modified tetraphenylethylene tecton, eleven kinetic-stable hydrogen-bonded organic frameworks (HOFs) with various shapes and two thermo-stable non-porous structures with rare perpendicular conformation are obtained. Multimode reversible structural transformations along with visible fluorescence output between porous and non-porous or between different porous forms is realized under different external stimuli. Furthermore, the collaborative of flexible framework and soft long-chain guests facilitate the relaxation from intrinsic blue emission to yellow emission in the excited state, which represents a strategy for generating white-light emission. The dynamic intermolecular interactions, facilitated by flexible molecular conformation and soft guests, diversifies the strategies of construction of versatile smart molecular frameworks.

Elucidation of Complex Dynamic Intermolecular Interactions in Membranes.

Biomembranes composed of various proteins and lipids play important roles in cellular functions, such as signal transduction and substance transport. In addition, some bioactive peptides and pathogenic proteins target membrane proteins and lipids to exert their effects. Therefore, an understanding of dynamic and complex intermolecular interactions among these membrane constituents is needed to elucidate their mechanisms. This review summarizes the major research carried out in the author's laboratory on how lipids and their inhomogeneous distributions regulate the structures and functions of antimicrobial peptides and Alzheimer's amyloid β-protein. Also, how to detect transmembrane helix-helix and membrane protein-protein interactions and how they are modulated by lipids are discussed.

Galectin-3 N-terminal tail prolines modulate cell activity and glycan-mediated oligomerization/phase separation

Galectin-3 (Gal-3) has a long, aperiodic, and dynamic proline-rich N-terminal tail (NT). The functional role of the NT with its numerous prolines has remained enigmatic since its discovery. To provide some resolution to this puzzle, we individually mutated all 14 NT prolines over the first 68 residues and assessed their effects on various Gal-3-mediated functions. Our findings show that mutation of any single proline (especially P37A, P55A, P60A, P64A/H, and P67A) dramatically and differentially inhibits Gal-3-mediated cellular activities (i.e., cell migration, activation, endocytosis, and hemagglutination). For mechanistic insight, we investigated the role of prolines in mediating Gal-3 oligomerization, a fundamental process required for these cell activities. We showed that Gal-3 oligomerization triggered by binding to glycoproteins is a dynamic process analogous to liquid-liquid phase separation (LLPS). The composition of these heterooligomers is dependent on the concentration of Gal-3 as well as on the concentration and type of glycoprotein. LLPS-like Gal-3 oligomerization/condensation was also observed on the plasma membrane and disrupted endomembranes. Molecular- and cell-based assays indicate that glycan binding-triggered Gal-3 LLPS (or LLPS-like) is driven mainly by dynamic intermolecular interactions between the Gal-3 NT and the carbohydrate recognition domain (CRD) F-face, although NT-NT interactions appear to contribute to a lesser extent. Mutation of each proline within the NT differentially controls NT-CRD interactions, consequently affecting glycan binding, LLPS, and cellular activities. Our results unveil the role of proline polymorphisms (e.g., at P64) associated with many diseases and suggest that the function of glycosylated cell surface receptors is dynamically regulated by Gal-3.

Effect of high intensity ultrasound on gelation properties of silver carp surimi with different salt contents

Surimi from silver carp with different salt contents (0–5%) was obtained treated by high intensity ultrasound (HIU, 100 kHz 91 W·cm−2). The gelation properties of samples were evaluated by puncture properties, microstructures, water-holding capacity, dynamic rheological properties and intermolecular interactions. As the salt content increased from 0 to 5%, gel properties of surimi without HIU significantly improved. For samples with low-salt (0–2% NaCl) content, HIU induced obvious enhancement in breaking force and deformation. HIU promoted the protein aggregation linked by SS bonds, hydrophobic interactions and non-disulfide covalent bonds in surimi gels with low-salt content. Moreover, microstructures of HIU surimi gels with low-salt content were more compact than those of the corresponding control samples. HIU also improved the gelation properties of surimi with 3% NaCl to an extent. However, for high-salt (4–5% NaCl) samples, HIU decreased the breaking force and deformation of surimi gels due to the degradation of proteins suggested by increased TCA-soluble peptides. In conclusion, HIU effectively improved the gelation properties of surimi with low-salt content (0–2% NaCl), but was harmful for high-salt (4–5% NaCl) surimi. This might provide the theoretical basis for the production of low-salt surimi gels.

Dynamic intermolecular interactions through hydrogen bonding of water promote heat conduction in hydrogels

Dynamic intermolecular forces through hydrogen bonding between water and polymer chains are shown to enhance thermal transport in soft materials.

Modulating and probing the dynamic intermolecular interactions in plasmonic molecule-pair junctions.

Reversible intermolecular interactions play critical roles in nature. However, it is still challenging to monitor the dynamic intermolecular interactions at the single-molecule level in aqueous solution. Here, we studied the dynamic changes of intermolecular interactions at the carboxyl/carboxyl interfaces between a pair of molecules trapped in a plasmonic nanocavity formed between a gold nanoparticle (GNP) and a gold nanoelectrode (GNE). The development of intermolecular interactions, including the appearance of hydrogen bonds (h-bonds), during and after single GNP collision events on the GNE, was monitored by time-resolved surface-enhanced Raman spectroscopy at a tens of milliseconds time resolution. Spectral fingerprints of the carboxyl group corresponding to non-specific intermolecular interactions and h-bonds are identified. Furthermore, we demonstrated that the strength of intermolecular interaction could be mechanically modulated by changing the applied bias at the GNE, which resulted in small and controllable changes in the nanogap distance. Unlike non-specific intermolecular interactions, the intermolecular h-bonds can only be formed stochastically and are more sensitive to the gap distance modulation. This report demonstrates a new approach to modulate and probe intermolecular interactions within nanogaps.

Dynamic Intermolecular Interactions Control Adsorption from Mixtures of Natural Organic Matter and Protein onto Titanium Dioxide Nanoparticles.

Engineered nanoparticles (NPs) will obtain macromolecular coatings in environmental systems, changing their subsequent interactions. The matrix complexity inherent in natural waters and wastewaters greatly complicates prediction of the corona formation. Here, we investigate corona formation on titanium dioxide (TiO2) NPs from mixtures of natural organic matter (NOM) and a protein, bovine serum albumin (BSA), to thoroughly probe the role of mixture interactions in the adsorption process. Fundamentally different coronas were observed under different NP exposure conditions and time scales. In mixtures of NOM and protein, the corona composition was kinetically determined, and the species initially coadsorbed but were ultimately limited to monolayers. On the contrary, sequential exposure of the NPs to pure solutions of NOM and protein resulted in extensive multilayer formation. The intermolecular complexation between NOM and BSA in solution and at the NP surface was the key mechanism controlling these distinctive adsorption behaviors, as determined by size exclusion chromatography (SEC) and in situ attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. Overall, this study demonstrates that dynamic intermolecular interactions and the history of the NP surface must be considered together to predict corona formation on NPs in complex environmental media.

PH-Responsive Emulsions with Supramolecularly Assembled Shells

Herein, we describe a novel and simple pH-switchable oil-in-water emulsion system prepared by intermolecular assembly of an amino-amide and a trace amount of citric acid. The resultant supramolecular complex, which demonstrated highly pH-responsive properties, was characterized with various techniques, including attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, ultraviolet–visible (UV–vis) spectroscopy, zeta potential, dynamic light scattering (DLS), surface tension, and interfacial tension. The switchable cyles between emulsification-demulsification states via adjusting the pH through the addition of acid or base were demonstrated with several types of oils. While emulsion was very stable at a pH of 2.2; a rapid phase separation was observed at and above pH of 5.5. Upon adjusting pH back to 2.2, stable emulsion could be re-assembled via dynamic intermolecular interactions. Such pH-triggered emulsification and demulsification cycles could be switched at least five times. T...

Skin-Inspired Electronics: An Emerging Paradigm.

Future electronics will take on more important roles in people's lives. They need to allow more intimate contact with human beings to enable advanced health monitoring, disease detection, medical therapies, and human-machine interfacing. However, current electronics are rigid, nondegradable and cannot self-repair, while the human body is soft, dynamic, stretchable, biodegradable, and self-healing. Therefore, it is critical to develop a new class of electronic materials that incorporate skinlike properties, including stretchability for conformable integration, minimal discomfort and suppressed invasive reactions; self-healing for long-term durability under harsh mechanical conditions; and biodegradability for reducing environmental impact and obviating the need for secondary device removal for medical implants. These demands have fueled the development of a new generation of electronic materials, primarily composed of polymers and polymer composites with both high electrical performance and skinlike properties, and consequently led to a new paradigm of electronics, termed "skin-inspired electronics". This Account covers recent important advances in skin-inspired electronics, from basic material developments to device components and proof-of-concept demonstrations for integrated bioelectronics applications. To date, stretchability has been the most prominent focus in this field. In contrast to strain-engineering approaches that extrinsically impart stretchability into inorganic electronics, intrinsically stretchable materials provide a direct route to achieve higher mechanical robustness, higher device density, and scalable fabrication. The key is the introduction of strain-dissipation mechanisms into the material design, which has been realized through molecular engineering (e.g., soft molecular segments, dynamic bonds) and physical engineering (e.g., nanoconfinement effect, geometric design). The material design concepts have led to the successful demonstrations of stretchable conductors, semiconductors, and dielectrics without sacrificing their electrical performance. Employing such materials, innovative device design coupled with fabrication method development has enabled stretchable sensors and displays as input/output components and large-scale transistor arrays for circuits and active matrixes. Strategies to incorporate self-healing into electronic materials are the second focus of this Account. To date, dynamic intermolecular interactions have been the most effective approach for imparting self-healing properties onto polymeric electronic materials, which have been utilized to fabricate self-healing sensors and actuators. Moreover, biodegradability has emerged as an important feature in skin-inspired electronics. The incorporation of degradable moieties along the polymer backbone allows for degradable conducting polymers and the use of bioderived materials has led to the demonstration of biodegradable functional devices, such as sensors and transistors. Finally, we highlight examples of skin-inspired electronics for three major applications: prosthetic e-skins, wearable electronics, and implantable electronics.

An anti-DNA antibody prefers damaged dsDNA over native

DNA–protein interactions, including DNA–antibody complexes, have both fundamental and practical significance. In particular, antibodies against double-stranded DNA play an important role in the pathogenesis of autoimmune diseases. Elucidation of structural mechanisms of an antigen recognition and interaction of anti-DNA antibodies provides a basis for understanding the role of DNA-containing immune complexes in human pathologies and for new treatments. Here we used Molecular Dynamic simulations of bimolecular complexes of a segment of dsDNA with a monoclonal anti-DNA antibody’s Fab-fragment to obtain detailed structural and physical characteristics of the dynamic intermolecular interactions. Using a computationally modified crystal structure of a Fab–DNA complex (PDB: 3VW3), we studied in silico equilibrium Molecular Dynamics of the Fab-fragment associated with two homologous dsDNA fragments, containing or not containing dimerized thymine, a product of DNA photodamage. The Fab-fragment interactions with the thymine dimer-containing DNA was thermodynamically more stable than with the native DNA. The amino acid residues constituting a paratope and the complementary nucleotide epitopes for both Fab–DNA constructs were identified. Stacking and electrostatic interactions were shown to play the main role in the antibody–dsDNA contacts, while hydrogen bonds were less significant. The aggregate of data show that the chemically modified dsDNA (containing a covalent thymine dimer) has a higher affinity toward the antibody and forms a stronger immune complex. These findings provide a mechanistic insight into formation and properties of the pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus, associated with skin photosensibilization and DNA photodamage.

Молекулярная динамика иммунного комплекса ДНК, содержащей фотоаддукт, с Fab-фрагментом антитела к ДНК

Antibodies to DNA play an important role in the pathogenesis of autoimmune diseases. The elucidation of structural mechanisms of both the antigen recognition and the interaction of anti-DNA antibodies with DNA will help to understand the role of DNA-containing immune complexes in various pathologies and can provide a basis for new treatment modalities. Moreover, the DNA-antibody complex is an analog of specific intracellular DNA-protein interactions. In this work, we used in silico molecular dynamic simulations of bimolecular complexes of the dsDNA segment containing the Fab fragment of an anti-DNA antibody to obtain the detailed thermodynamic and structural characteristics of dynamic intermolecular interactions. Using computationally modified crystal structure of the Fab-DNA complex (PDB ID: 3VW3), we studied the equilibrium molecular dynamics of the 64M-5 antibody Fab fragment associated with the dsDNA fragment containing the thymine dimer, the product of DNA photodamage. Amino acid residues that constitute paratopes and the complementary nucleotide epitopes for the Fab-DNA construct were identified. Stacking and electrostatic interactions were found to play the main role in mediating the most specific antibody-dsDNA contacts, while hydrogen bonds were less significant. These findings may shed light on the formation and properties of pathogenic anti-DNA antibodies in autoimmune diseases, such as systemic lupus erythematosus associated with skin photosensitivity and DNA photodamage.

Quantitative FRET measurement using emission-spectral unmixing with independent excitation crosstalk correction.

Quantification of fluorescence resonance energy transfer (FRET) needs at least two external samples, an acceptor-only reference and a linked FRET reference, to calibrate fluorescence signal. Furthermore, all measurements for references and FRET samples must be performed under the same instrumental conditions. Based on a novel notion to predetermine the molar extinction coefficient ratio (RC ) of acceptor-to-donor for the correction of acceptor excitation crosstalk, we present here a robust and independent emission-spectral unmixing FRET methodology, Iem-spFRET, which can simultaneously measure the E and RC of FRET sample without any external references, such that Iem-spFRET circumvents the rigorous restriction of keeping the same imaging conditions for all FRET experiments and thus can be used for the direct measurement of FRET sample. We validate Iem-spFRET by measuring the absolute E and RC values of standard constructs with different acceptor-to-donor stoichiometry expressed in living cells. Our results demonstrate that Iem-spFRET is a simple and powerful tool for real-time monitoring the dynamic intermolecular interaction within single living cells.