Graphene nanosheets are impermeable to chemical molecules and electrical conductivity. Thus, they are attractive candidates to enhance an epoxy zinc rich coating with a significant anticorrosion ...performance. Several studies focus on investigating the role of graphene in reinforcing the corrosion resistance of the coatings. However, there is a paucity of study that analyzing the anticorrosion relationship between the feature of graphene and epoxy zinc rich coating. The present study reported on epoxy zinc rich coatings with enhanced anticorrosion performance via embedding reduced graphene oxide/graphene oxide (rGO/GO) nanosheets. Thus, rGO and GO were prepared from natural graphite powder via the modified Hummers method. The results of Raman, XPS, FT-IR, SPM, and TEM analyses revealed the quintessential structure and morphology of rGO and GO. In addition, results from electrochemical measurements and the scanning vibrating electrode technique indicated that rGO effectively enhanced the cathodic protection duration of epoxy zinc rich coatings. rGO nanosheets exhibited dual functions that were identified in two aspects. First, the impermeable barrier role was exerted by including prepared rGO nanosheets into the polymer matrix. Second, superior electrical conductivity was utilized since the rGO nanosheets improved the efficiency of the electrical connection between the zinc particles and steel substrate.
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•Well-designed rGO nanosheets were used for enhancing anticorrosion.•rGO can enhance the cathodic protection duration of epoxy zinc rich coating.•rGO endowed composite coating exhibited optimal anticorrosion capability.•SVET confirmed the cathodic protection property of the coating.
Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins. For example, the association ...of membrane proteins with proteins on different cells (trans-interactions) can drive the oligomerization of proteins on the same cell (cis-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation. A finding of general relevance is that changes in interdomain motion on trans-binding have a crucial role in driving the lateral, cis-, clustering of adhesion receptors.
Abstract
Background
Proteins form various complexes to carry out their versatile functions in cells. The dynamic properties of protein complex formation are mainly characterized by the association ...rates which measures how fast these complexes can be formed. It was experimentally observed that the association rates span an extremely wide range with over ten orders of magnitudes. Identification of association rates within this spectrum for specific protein complexes is therefore essential for us to understand their functional roles.
Results
To tackle this problem, we integrate physics-based coarse-grained simulations into a neural-network-based classification model to estimate the range of association rates for protein complexes in a large-scale benchmark set. The cross-validation results show that, when an optimal threshold was selected, we can reach the best performance with specificity, precision, sensitivity and overall accuracy all higher than 70%. The quality of our cross-validation data has also been testified by further statistical analysis. Additionally, given an independent testing set, we can successfully predict the group of association rates for eight protein complexes out of ten. Finally, the analysis of failed cases suggests the future implementation of conformational dynamics into simulation can further improve model.
Conclusions
In summary, this study demonstrated that a new modeling framework that combines biophysical simulations with bioinformatics approaches is able to identify protein–protein interactions with low association rates from those with higher association rates. This method thereby can serve as a useful addition to a collection of existing experimental approaches that measure biomolecular recognition.
Ligands in the tumor necrosis factor (TNF) superfamily are one major class of cytokines that bind to their corresponding receptors in the tumor necrosis factor receptor (TNFR) superfamily and ...initiate multiple intracellular signaling pathways during inflammation, tissue homeostasis, and cell differentiation. Mutations in the genes that encode TNF ligands or TNFR receptors result in a large variety of diseases. The development of therapeutic treatment for these diseases can be greatly benefitted from the knowledge on binding properties of these ligand-receptor interactions. In order to complement the limitations in the current experimental methods that measure the binding constants of TNF/TNFR interactions, we developed a new simulation strategy to computationally estimate the association and dissociation between a ligand and its receptor. We systematically tested this strategy to a comprehensive dataset that contained structures of diverse complexes between TNF ligands and their corresponding receptors in the TNFR superfamily. We demonstrated that the binding stabilities inferred from our simulation results were compatible with existing experimental data. We further compared the binding kinetics of different TNF/TNFR systems, and explored their potential functional implication. We suggest that the transient binding between ligands and cell surface receptors leads into a dynamic nature of cross-membrane signal transduction, whereas the slow but strong binding of these ligands to the soluble decoy receptors is naturally designed to fulfill their functions as inhibitors of signal activation. Therefore, our computational approach serves as a useful addition to current experimental techniques for the quantitatively comparison of interactions across different members in the TNF and TNFR superfamily. It also provides a mechanistic understanding to the functions of TNF-associated cell signaling pathways.
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The corrosion-resistant hybrid films based on fluorocarbon polymer and single layer graphene were prepared. The hydrophobic fluorocarbon film covered the defect on graphene coated Cu, ...which inhibited the direct corrosion at the defect site, and forbade the galvanic corrosion between graphene and Cu substrate. The results confirmed that the hybrid coatings showed much better anti-corrosion performance. Electrochemical impedance spectroscopy measurements revealed that the hybrid coatings provided an effective physical barrier against the corrosive medium. The finding here is critical in designing hybrid protective coatings with the defect-repaired structure on the graphene coated Cu.
The activation and differentiation of T-cells are mainly directly by their co-regulatory receptors. T lymphocyte-associated protein-4 (CTLA-4) and programed cell death-1 (PD-1) are two of the most ...important co-regulatory receptors. Binding of PD-1 and CTLA-4 with their corresponding ligands programed cell death-ligand 1 (PD-L1) and B7 on the antigen presenting cells (APC) activates two central co-inhibitory signaling pathways to suppress T cell functions. Interestingly, recent experiments have identified a new cis-interaction between PD-L1 and B7, suggesting that a crosstalk exists between two co-inhibitory receptors and the two pairs of ligand-receptor complexes can undergo dynamic oligomerization. Inspired by these experimental evidences, we developed a coarse-grained model to characterize the assembling of an immune complex consisting of CLTA-4, B7, PD-L1 and PD-1. These four proteins and their interactions form a small network motif. The temporal dynamics and spatial pattern formation of this network was simulated by a diffusion-reaction algorithm. Our simulation method incorporates the membrane confinement of cell surface proteins and geometric arrangement of different binding interfaces between these proteins. A wide range of binding constants was tested for the interactions involved in the network. Interestingly, we show that the CTLA-4/B7 ligand-receptor complexes can first form linear oligomers, while these oligomers further align together into two-dimensional clusters. Similar phenomenon has also been observed in other systems of cell surface proteins. Our test results further indicate that both co-inhibitory signaling pathways activated by B7 and PD-L1 can be down-regulated by the new cis-interaction between these two ligands, consistent with previous experimental evidences. Finally, the simulations also suggest that the dynamic and the spatial properties of the immune complex assembly are highly determined by the energetics of molecular interactions in the network. Our study, therefore, brings new insights to the co-regulatory mechanisms of T cell activation.
The interactions between membrane receptors and extracellular ligands control cell-cell and cell-substrate adhesion, and environmental responsiveness by representing the initial steps of cell ...signaling pathways. These interactions can be spatial-temporally regulated when different extracellular ligands are tethered. The detailed mechanisms of this spatial-temporal regulation, including the competition between distinct ligands with overlapping binding sites and the conformational flexibility in multi-specific ligand assemblies have not been quantitatively evaluated. We present a new coarse-grained model to realistically simulate the binding process between multi-specific ligands and membrane receptors on cell surfaces. The model simplifies each receptor and each binding site in a multi-specific ligand as a rigid body. Different numbers or types of ligands are spatially organized together in the simulation. These designs were used to test the relation between the overall binding of a multi-specific ligand and the affinity of its cognate binding site. When a variety of ligands are exposed to cells expressing different densities of surface receptors, we demonstrated that ligands with reduced affinities have higher specificity to distinguish cells based on the relative concentrations of their receptors. Finally, modification of intramolecular flexibility was shown to play a role in optimizing the binding between receptors and ligands. In summary, our studies bring new insights to the general principles of ligand-receptor interactions. Future applications of our method will pave the way for new strategies to generate next-generation biologics.
The self-assembly of viral capsids is an essential step to the formation of infectious viruses. Elucidating the kinetic mechanisms of how a capsid or virus-like particle assembles could advance our ...knowledge about the viral lifecycle, as well as the general principles in self-assembly of biomaterials. However, current understanding of capsid assembly remains incomplete for many viruses due to the fact that the transient intermediates along the assembling pathways are experimentally difficult to be detected. In this paper, we constructed a new multiscale computational framework to simulate the self-assembly of virus-like particles. We applied our method to the coat proteins of bacteriophage MS2 as a specific model system. This virus-like particle of bacteriophage MS2 has a unique feature that its 90 sequence-identical dimers can be classified into two structurally various groups: one is the symmetric CC dimer, and the other is the asymmetric AB dimer. The homotypic interactions between AB dimers result in a 5-fold symmetric contact, while the heterotypic interactions between AB and CC dimers result in 6-fold symmetric contact. We found that the assembly can be described as a physical process of phase transition that is regulated by various factors such as concentration and specific stoichiometry between AB and CC dimers. Our simulations also demonstrate that heterotypic and homotypic interfaces play distinctive roles in modulating the assembling kinetics. The interaction between AB and CC dimers is much more dynamic than that between two AB dimers. We therefore suggest that the alternate growth of viral capsid through the heterotypic dimer interactions dominates the assembling pathways. This is, to the best of our knowledge, the first multiscale model to simulate the assembling process of coat proteins in bacteriophage MS2. The generality of this approach opens the door to its further applications in assembly of other viral capsids, virus-like particles, and novel drug delivery systems.
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By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved ...in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.
In the present work, the novel anodic oxide film (AOF) with self-sealing layer was successfully fabricated on 2024Al alloys by using an improved anodic oxidation method. The presence of the ...self-sealing layer on the porous layer of AOF was verified by Field emission scanning electron micro scope. Confocal laser scanning microscope (CLSM) and X-ray photoelectron spectroscopy (XPS) were used to evaluate the morphology and the corrosion products of the AOF after salt spray test. The microhardness test showed that the self-sealing AOFs still displayed high hardness even after salt spray test. Electrochemical test and salt spray test results illustrated the excellent corrosion performance of the novel structured self-sealing anodic oxide film (SAOF) compared with common porous AOFs. The narrow diameter makes it difficult for chlorine ions ingress into the pores of SAOFs. The self-sealing layer played an important role in protecting the SAOF from corrosion.
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