Chain Conformation Research Articles

Quantitative Examination and Mechanistic Insights of Polymer Chain Conformation Confined in Nanopores by Time-Resolved Fluorescence Resonance Energy Transfer

Quantitative Examination and Mechanistic Insights of Polymer Chain Conformation Confined in Nanopores by Time-Resolved Fluorescence Resonance Energy Transfer

Multiscale Analyses of Strain-Enhanced Charge Transport in Conjugated Polymers.

The advancement of flexible and wearable electronics relies on semiconducting polymers that can endure mechanical deformation while maintaining high electrical performance under strain. In this study, we demonstrate that fine-tuning backbone rigidity through the molecular design of donor moieties significantly enhances both the mechanical and charge transport properties of diketopyrrolopyrrole (DPP)-based polymers. Specifically, the flexible DPP-4T (quaterthiophene) exhibited a persistence length of 20.4 nm in solution, while DPP-DTT (dithienothiophene) showed a longer persistence length of 32.8 nm due to its stiff backbone, as confirmed by small-angle neutron scattering and Monte Carlo simulations. This flexibility enabled DPP-4T to achieve a crack-onset strain exceeding 100% via the film-on-elastomer method and a fracture strain of over 30% in quasi-free-standing films. Additionally, DPP-4T demonstrated a 180% increase in hole mobility at 80% strain, driven by strain-induced chain alignment and backbone planarization. Utilizing a range of characterization techniques, including ultraviolet-visible (UV-vis) spectroscopy, grazing incidence X-ray diffraction (XRD), and Raman spectroscopy, we characterized structural changes at multiple length scales under applied tensile strain. Notably, strain induced a transformation in chain conformation from a twisted to a flat structure, reducing the hopping energy barrier and enhancing charge transport. These structural rearrangements are crucial for sustaining efficient charge transport and ensuring the reliability of electronic performance under mechanical stress.

Molecular Modeling of Glycosylated Catalytic Domain of Human Carbonic Anhydrase IX.

Glycans exhibit significant structural diversity due to the flexibility of glycosidic bonds linking their constituent monosaccharides and the formation of numerous hydrogen bonds. The present work searches a simulated ensemble of glycan chain conformations attached to the catalytic domain of N-glycosylated human carbonic anhydrase IX (HCA IX-c) to identify conformations pointed away or back-folded toward the protein surface guided by different amino acid residues. A series of classical molecular dynamics (MD) simulation studies for a total of 30 μs followed by accelerated MD simulations for a total of 2 μs have been performed using two different force fields to capture varying degrees of fluctuations of both glycan chain and HCA IX. From the underlying free energy profile and kinetics derived using hidden Markov state model, several stable glycan orientations are identified that extend away from the protein surface and convert among each other with rate constants of the order 107-1010 S-1. Most importantly, we have identified a rare glycan conformation which reaches close to a catalytically important amino acid residue, Glu-106. We further enlist the protein residues that couple such less frequent event of the glycan chain back-folding toward the surface of the protein.

Molecular dynamics simulation: Effect of sulfation on the structure of curdlan triple helix in aqueous solution

In this work, by using molecular dynamics simulations, we elucidate the effect of sulfation substitution on the stability of the curdlan triple helix structure. The simulation results indicate that the stability of the triple helix structure is significantly influenced by the sites of sulfation substitution. The substitution at the O2 site directly disrupts the hydrogen bonding network between the triple helix chains, significantly destroying the triple helix conformation. When substitutions occur at both the O4 and O6 sites simultaneously (O4,6), the electrostatic repulsion between numerous sulfate groups introduces considerable energy perturbation to the triple helix, leading to alterations in the glucan chain conformation and consequent destabilization of the triple helix structure. Meanwhile, we find that even if the sulfation substitution is performed at the same substitution sites, the difference in the degree of substitution also has an impact on the triple helix stability. The resistance of the triple helix to sulfation substitution at O2 is weak, and low degree of substitution can lead to the unwinding of the triple helix. However, it demonstrates higher resistance to substitution at O4,6 where only higher degree of substitution results in triple helix destabilization.

The Structure Characterization of Polysaccharides from Codonopsis pilosula and the Structure-activity Relationship with Immune-regulation on THP-1 Cells.

In recent years, polysaccharides from Codonopsis pilosula (CPs) have received increasing attention for their excellent behaviors in immune-regulation. However, the relationship between the structure and immunomodulatory activity has rarely been reported. In this work, four fractions purified from crude CPs (CPW, CPS0.2, CPS0.5, CPS1) by chromatographic column separation were explored with both structure and immunomodulatory effects by THP-1 cells. The results showed that the monosaccharide composition, chain conformation, molecular weight (Mw) and aggregated state of CPs were different. At the same time, the immunomodulatory effects of CPs were also varied depend on structure differences, as indicated by the released cytokines of TNF-α and IL-1β by LPS-induced THP-1 cells. Finally, we summarized and concluded that the spherical structure and smaller particle size of CPs were the key factors attributed to better immune-enhancing effects. The results showed that the monosaccharide combination differences of polysaccharides might lead to anti-inflammatory or pro-inflammatory activity. Moreover, the higher percentage of glucose, the relatively large particle size, as well as the extended chain conformation of CPs might be the key factors attributed to better immune-enhancing effects. This study aims to provide a theoretical basis for establishing the structure-activity relationship of CPs.

Integrating 19F Distance Restraints for Accurate Protein Structure Determination by Magic Angle Spinning NMR Spectroscopy.

Traditional protein structure determination by magic angle spinning (MAS) solid-state NMR spectroscopy primarily relies on interatomic distances up to 8 Å, extracted from 13C-, 15N-, and 1H-based dipolar-based correlation experiments. Here, we show that 19F fast (60 kHz) MAS NMR spectroscopy can supply additional, longer distances. Using 4F-Trp,U-13C,15N crystalline Oscillatoria agardhii agglutinin (OAA), we demonstrate that judiciously designed 2D and 3D 19F-based dipolar correlation experiments such as (H)CF, (H)CHF, and FF can yield interatomic distances in the 8-16 Å range. Incorporation of fluorine-based restraints into structure calculation improved the precision of Trp side chain conformations as well as regions in the protein around the fluorine containing residues, with notable improvements observed for residues in proximity to the Trp pairs (W10/W17 and W77/W84) in the carbohydrate-binding loops, which lacked sufficient long-range 13C-13C distance restraints. Our work highlights the use of fluorine and 19F fast MAS NMR spectroscopy as a powerful structural biology tool.

Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis.

Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound 4 (INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, in vitro and in vivo preclinical studies revealed favorable in vitro and in vivo DMPK properties. Results from multiple cell-based and animal models proved that compound 4 exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound 4 are underway for the treatment of idiopathic pulmonary fibrosis (IPF).

Potent and Protease Resistant Azapeptide Agonists of the GLP‐1 and GIP Receptors

AbstractThe gut‐derived peptide hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP‐1 receptor (GLP‐1R) and dual agonists of GLP‐1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase‐4 (DPP4), that catalyzes rapid removal of the two N‐terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza‐amino acids, that are bioisosteric replacements for α‐amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza‐amino acid can populate the same conformational space that GLP‐1 adopts when bound to the GLP‐1R. The insertion of an aza‐amino acid at the second position from the N‐terminus in semaglutide and in a dual agonist of GLP‐1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling.

A polysaccharide with a triple helix structure from Agaricus bisporus: Characterization and anti-colon cancer activity

In this study, A polysaccharide WAAP-2 (121 kDa) with a triple-helical structure was isolated and purified from Agaricus bisporus for the first time. The physicochemical properties, structural characteristics and anti-colon cancer activity were preliminarily investigated. The primary structure indicated that WAAP-2 was composed of mannose, glucose and galactose and determined the position of the linkage between monosaccharide residues. The advanced structure revealed that WAAP-2 has a triple helix and tangled chain conformation. In the anti-colon cancer activity investigation, WAAP-2 exerted an apoptosis-inducing effect by causing HT-29 cell cycle arrest in S phase. WAAP-2 promoted HT-29 cell apoptosis by up-regulating the expression of Caspase-3 and Bax proteins while down-regulating the expression of Bcl-2 protein. Besides, WAAP-2 could inhibit the migration and invasion of colorectal cancer cells by inducing E-cadherin expression and inhibiting Vimentin expression to affect epithelial mesenchymal transition. This paper is of importance for the application of WAAP-2, a triple-helical structural polysaccharide from Agaricus bisporus, to low-toxicity anti-colon cancer drugs.

Influence of functional group structures in nucleating agents on the crystallization behavior of poly(ethylene terephthalate)

AbstractNucleating agents are crucial for modifying semi‐crystalline polymers, but the impact of different end‐group structures on crystallization behavior remains unclear. This study synthesized succinic dihydrazide nucleating agents with various end groups (methyl, ethyl, and tert‐butyl) for PET composite materials. The tert‐butyl‐terminated nucleating agent showed the best performance, increasing the crystallization peak temperature to 203.8°C, crystallinity to 27.3%, and reducing half‐crystallization time to 2.8 min at 220°C. It also enhanced the impact strength to 47.2 kJ·m−2 and flexural modulus to 2623 MPa, while improving Vicat softening temperature and heat distortion temperature by 41 and 8°C, respectively. The results from FTIR and Raman Spectroscopy indicate that the interactions between the end groups of the nucleating agent and the CH bonds in the PET structure, the π–π interactions between the nucleating agent and the PET molecular structure, as well as the modulation of the PET chain conformation by the nucleating agent, are the primary factors contributing to the enhanced crystallinity of PET. This study provides a new approach for designing efficient nucleating agents for high‐performance materials.

Unexpected self-healing acceleration within urethane networks: lignosulfonate mediation of ionic and hydrogen bonds for ultra-strong recyclable elastomers

Stiff structures are generally considered detrimental to the materials’ self-healing efficiency because of the rigid conformation and restricted motion of the molecular chains. However, in this study, an unexpected acceleration in self-healing was observed in a urethane network when lignosulfonate, a bio-based stiff structure with stiff benzene rings, was introduced into the polyurethane matrix. An extraordinary increase in mechanical properties was achieved with just 3 wt% lignosulfonate added to the pristine sample, including a strength increase from 16.24 MPa to 42.89 MPa and elongation at break from 390% to 602%. Importantly, this significant enhancement in mechanical properties was accompanied by a notable acceleration in healing time efficiency, which increased by up to 44% compared to the pristine sample. This unique behavior can be attributed to the mediation of lignosulfonate on the ionic bonds between lignosulfonate and the urethane segment, as well as the hydrogen bonds formed within the urethane segments. This mediation ensures ultra-high strength without compromising the self-healing capacity and opens a way for accelerating elastomers self-healing efficiency through lignosulfonate, a readily available biomass-derived material. In addition, the addition of lignosulfonates gives the elastomer some Anti-UV performance.

A foundational framework for the mesoscale modeling of dynamic elastomers and gels

Discrete mesoscale network models, in which explicitly modeled polymer chains are replaced by implicit pairwise potentials, are capable of predicting the macroscale mechanical response of polymeric materials such as elastomers and gels, while offering greater insight into microstructural phenomena than constitutive theory or macroscale experiments alone. However, whether such mesoscale models accurately represent the molecular structures of polymer networks requires investigation during their development, particularly in the case of dynamic polymers that restructure in time. We here introduce and compare the topological and mechanical predictions of an idealized, reduced-order mesoscale approach in which only tethered dynamic bonding sites and crosslinks in a polymer’s backbone are explicitly modeled, to those of molecular theory and a Kremer-Grest, coarse-grained molecular dynamics approach. We find that for short chain networks (∼12 Kuhn lengths per chain segment) at intermediate polymer packing fractions, undergoing relatively slow loading rates (compared to the monomer diffusion rate), the mesoscale approach reasonably reproduces the chain conformations, bond kinetic rates, and ensemble stress responses predicted by molecular theory and the bead–spring model. Further, it does so with a 90% reduction in computational cost. These savings grant the mesoscale model access to larger spatiotemporal domains than conventional molecular dynamics, enabling simulation of large deformations as well as durations approaching experimental timescales (e.g., those utilized in dynamic mechanical analysis). While the model investigated is for monodisperse polymer networks in theta-solvent, without entanglement, charge interactions, long-range dynamic bond interactions, or other confounding physical effects, this work highlights the utility of these models and lays a foundational groundwork for the incorporation of such phenomena moving forward.

Evolution of [formula omitted]-spacing in clay with PEG bulk volume fraction and molecular weight: Theoretical and experimental study

In the pursuit of ensuring the sustainability of the construction sector and fortifying its resilience against climate change, scientists have dedicated significant efforts to explore new classes of innovative, affordable, and technologically advanced materials that exhibit high efficiency, thereby securing the future for generations to come. In this context, we have opted to produce clay-polymer ecosystems through the direct insertion process. The PEG2000/clay and PEG6000/clay composites underwent analysis using X-ray diffraction (XRD) techniques, revealing the evolution of dhklconcerning the PEG bulk volume fraction. The results indicate the presence of two adsorption cycles, each comprising three stages (dilute, two-dimensional semi-dilute, and plateau). Each cycle delineates the incorporation of a polymer layer into the interlayer spaces of clay minerals. To elucidate this adsorption process, we have proposed a model depicting PEG chain conformation in confined spaces, represented as both monolayer and bilayer configurations. The influence of PEG molecular weight is distinctly evident in the dhklevolution across various clay categories. Ultimately, the application of scaling theory to model the experimental results proves to be robust, offering a precise description of the three discussed regimes.

Regulatory effects of cyclodextrins on light-responsive phase transition behaviors of poly(N-isopropylacrylamide-co-N-(4-phenylazophenyl)methylacrylamide)

The physicochemical properties of light-responsive polymers have attracted widespread attention due to their ability to be precisely and conveniently modulated by light without additives or contact. Here, we report a thermo/light dual-responsive polymer, PNMA, synthesized through the free radical copolymerization of azobenzene derivative (mAzo) and N-isopropylacrylamide (NIPAM) monomers. By switching between 365 nm UV light and 450 nm visible light, the E/Z photoisomerization of the light-responsive mAzo can be reversibly controlled, and thereby adjusting the conformational changes of the PNMA polymer chain. Significantly, the stretching and contraction conformations of PNMA polymer chains can be manipulated by incorporating different types of cyclodextrins. A comprehensive comparative study was conducted to determine the light-controlled binding and dissociation processes between the azobenzene units and CDs (α-CD, β-CD and γ-CD), the influences of CDs on the photoisomerization kinetics and complexation constants of azobenzene with CDs, as well as the effect of CDs on the light-responsive phase transition behaviors of PNMA. Our results highlight the superior advantage of α-CD in constructing light-responsive systems with significant changes in hydrophilicity. Notably, by tuning the concentration of α-CD and the proportion of mAzo in PNMA, the range of light-induced thermosensitive response is significantly expanded. This study is the first to present a comparative study on the effects of three CDs on the thermo/light dual-responsive properties of polymer systems based on PNIPAM and azobenzene, providing new ideas for CD selection in the design and construction of advanced light-responsive materials based on light-responsive guest-host dissociation or hydrophilic changes of azobenzene/CD complexes.

Competitive effects of anion mobility and viscous forces on the interactions of hyaluronic acid and alginic acid with hofmeister salts

The specific ion effect takes into account the hydration, mobility, and kosmotropic/chaotropic effects. However, another important aspect to consider is the solution viscosity, which influences ion mobility. A limited number of publications have considered the impact of specific ion effects on polyelectrolytes. However, none of the studies have considered the viscous effect of polyelectrolytes. This study aims to investigate the impact of kosmotropic and chaotropic anions on negatively charged alginic acid and hyaluronic acid using dynamic light scattering, rheology, and molecular dynamic simulations. Different concentration regimes and the change in the chain conformations in these regimes, along with the viscosity scaling and impact of the salts on the polyelectrolytes, have been discussed. An interesting finding regarding the solution viscosity was reported. The solution viscosity leads to the reversal of the diffusivity and viscosity trend of the polymer with kosmotropes and chaotropes. A threshold is also identified above which viscous forces dominate. Specific ion effects dominate below the threshold. It was concluded that the specific ion effect shows a competitive nature with the viscous forces in the case of a high-viscosity polyelectrolyte solution, which becomes an important aspect to consider for unveiling such interactions. Prior knowledge of the conformations of polymers can be used for designing drug delivery/nutrient delivery systems and for understanding phase separation behavior. Considering the viscosity of polymer solution becomes an important factor which, in turn, impacts the anion's mobility and ultimately influences the polymer conformations.

Cellulose Fiber with Enhanced Mechanical Properties: The Role of Co-Solvents in Gel-like NMMO System.

Cellulose has garnered attention in the textile industry, but it exhibits limitations in applications that require high strength and modulus. In this study, regenerated cellulose fiber with enhanced mechanical properties was fabricated from a gel-like N-methylmorpholine N-oxide (NMMO)-cellulose solution by modulating the intermolecular interaction and conformation of the cellulose chains. To control the interaction, two types of co-solvents (dimethyl acetamide (DMAc) and dimethyl formamide (DMF)) were added to the cellulose solutions at varying concentrations (10, 20, and 30 wt%). Rheological analysis showed that the co-solvents reduced the solution viscosity by weakening intermolecular interactions. The calculated distance parameter (Ra) in Hansen space confirmed that the co-solvent disrupted intermolecular hydrogen bonding within cellulose chains. The solutions were spun into fiber via a simple wet spinning process and were characterized by X-ray diffraction (XRD) and universal testing machine (UTM). The addition of co-solvent led to an increased crystallinity index (C.I.) owing to the extended cellulose chains. The modulus of the resulting fiber was increased when the co-solvent concentration was 10 wt%, regardless of the co-solvent type. This study demonstrates the potential for enhancing the mechanical properties of cellulose-based products by modulating the conformation and interaction of cellulose chains through the addition of co-solvent.

All‐Atom Protein Sequence Design Based on Geometric Deep Learning

Designing sequences for specific protein backbones is a key step in creating new functional proteins. Here, we introduce GeoSeqBuilder, a deep learning framework that integrates protein sequence generation with side chain conformation prediction to produce the complete all‐atom structures for designed sequences. GeoSeqBuilder uses spatial geometric features from protein backbones and explicitly includes three‐body interactions of neighboring residues. GeoSeqBuilder achieves native residue type recovery rate of 51.6%, comparable to ProteinMPNN and other leading methods, while accurately predicting side chain conformations. We first used GeoSeqBuilder to design sequences for thioredoxin and a hallucinated three‐helical bundle protein. All the 15 tested sequences expressed as soluble monomeric proteins with high thermal stability, and the 2 high‐resolution crystal structures solved closely match the designed models. The generated protein sequences exhibit low similarity (minimum 23%) to the original sequences, with significantly altered hydrophobic cores. We further redesigned the hydrophobic core of glutathione peroxidase 4, and 3 of the 5 designs showed improved enzyme activity. Although further testing is needed, the high experimental success rate in our testing demonstrates that GeoSeqBuilder is a powerful tool for designing novel sequences for predefined protein structures with atomic details. GeoSeqBuilder is available at https://github.com/PKUliujl/GeoSeqBuilder

All-Atom Protein Sequence Design Based on Geometric Deep Learning.

Designing sequences for specific protein backbones is a keystep in creating new functional proteins. Here, we introduceGeoSeqBuilder, a deep learning framework that integratesprotein sequence generation with side chain conformationprediction to produce the complete all-atom structures fordesigned sequences. GeoSeqBuilder uses spatial geometricfeatures from protein backbones and explicitly includesthree-body interactions of neighboring residues. GeoSeqBuilderachieves native residue type recovery rate of 51.6%,comparable to ProteinMPNN and otherleadingmethods,while accurately predicting side chain conformations. Wefirst used GeoSeqBuilder to design sequences for thioredoxinand a hallucinated three-helical bundle protein. All the15 tested sequences expressed as soluble monomeric proteinswith high thermal stability, and the 2 high-resolutioncrystal structures solved closely match the designed models.The generated protein sequences exhibit low similarity(minimum 23%) to the original sequences, with significantlyaltered hydrophobic cores. We further redesigned the hydrophobiccore of glutathione peroxidase 4, and 3 of the 5designs showed improved enzyme activity. Although furthertesting is needed, the high experimental success ratein our testing demonstrates that GeoSeqBuilder is a powerfultool for designing novel sequences for predefined proteinstructures with atomic details. GeoSeqBuilder is availableat https://github.com/PKUliujl/GeoSeqBuilder.

The importance of initial extension rate on elasto-capillary thinning of dilute polymer solutions

This work focuses on inferring the molecular state of the polymer chain required to induce stress relaxation and the accurate measure of the polymer’s longest relaxation time in uniaxial stretching of dilute polymer solutions. This work is facilitated by the discovery that constant velocity applied at early times leads to initial constant extension rate before reaching the Rayleigh–Plateau instability. Such constant rate experiments are used to correlate initial stretching kinematics with the thinning dynamics in the final thinning regime. We show that there is a minimum initial strain-rate required to induce rate independent elastic effects, and measure the longest relaxation time of the material. Below the minimum extension rate, insufficient stretching of the chain is observed before capillary instability, such that the polymer stress is comparable to the capillary stress at long times and stress relaxation is not achieved. Above the minimum strain-rate, the chain reaches a critical stretch before instability, such that during the unstable filament thinning the polymer stress is significantly larger than the capillary stress and rate-independent stress relaxation is observed. Using a single relaxation mode FENE model, we show that the minimum strain rate leads to a required initial stretch of the chain before reaching the Rayleigh–Plateau limit. These results indicate that the chain conformation before entering the Rayleigh Instability Regime, and the stretching induced during the instability, determines the elastic behavior of the filament. Lastly, this work introduces a characteristic dimensionless group, called the stretchability factor, that can be used to quantitatively compare different materials based on the overall material deformation/kinematic behavior, not just the relaxation time. Overall, these results demonstrate a useful methodology to study the stretching of dilute solutions using a constant velocity stretching scheme.

Conformational Selection in Enzyme-Catalyzed Depolymerization of Bio-based Polyesters.

Enzymatic degradation of polymers holds promise for advancing towards a bio-based economy. However, bulky polymers presents challenges in accessibility for biocatalysts, hindering depolymerization reactions. Beyond the impact of crystallinity, polymer chains can reside in different conformations affecting binding efficiency to the enzyme. We previously showed that the gauche and trans chain conformers associated with crystalline and amorphous regions of the synthetic polyethylene terephthalate (PET) display different affinity to PETase, thus affecting the depolymerization rate. However, structural-function relationships for biopolymers remain poorly understood in biocatalysis. In this study, we explored biodegradation of by-us previously synthesized bio-polyesters made from a rigid bicyclic chiral terpene-based diol and copolymerized with various renewable diesters. Herein, four of those polyesters spanning from semi-aromatic to aliphatic were subjected to enzymatic degradations in concert with induced-fit docking (IFD) analyses. Our findings demonstrate the importance of conformational selection in enzymatic depolymerization of biopolymers. A straight or twisted conformation of the polymer chain is crucial in biocatalytic degradation by showing different affinities to enzyme ground-state conformers. This work highlights the importance of considering the conformational match between the polymer and the enzyme to optimize the biocatalytic degradation efficiency of biopolymers, providing valuable insights for the development of sustainable bioprocesses.