Ion-Cage Interpretation for the Structural and Dynamic Changes of Ionic Liquids under an External Electric Field

In many applications, ionic liquids (ILs) work in a nonequilibrium steady state driven by an external electric field. However, how the electric field changes the structure and dynamics of ILs and its underlying mechanism still remain poorly understood. In this paper, coarse-grained molecular dynamics simulations were performed to investigate the structure and dynamics of 1-ethyl-3-methylimidazolium nitrate ([EMIm]­[NO₃]) under a static electric field. The ion cage structure was found to play an essential role in determining the structural and dynamic properties of the IL system. With a weak or moderate electric field (0–10⁷ V/m), the external electric field is too weak to modify the ion cage structure in an influential way and thus the changes of structural and dynamic properties are negligible. With a strong electric field (10⁷–10⁹ V/m) applied, ion cages expand and deform apparently, leading to the increase of ion mobility and self-diffusion coefficient with electric field, and the self-diffusion of ions along the electric field becomes faster than the other two directions due to the anisotropic deformation of ion cages. In addition, the Einstein relation connecting diffusion and mobility breaks down at strong electric fields, and it also breaks down for a single ion species even at moderate electric fields (linear-response region)

Metastable State during Melting and Solid–Solid Phase Transition of [C_<i>n</i>Mim][NO₃] (<i>n</i> = 4–12) Ionic Liquids by Molecular Dynamics Simulation

We simulate the heating process of ionic liquids [C_<i>n</i>Mim]­[NO₃] (<i>n</i> = 4, 6, 8, 10, 12), abbreviated as C_<i>n</i>, by means of molecular dynamics (MD) simulation starting from a manually constructed triclinic crystal structure composed of polar layers containing anions and cationic head groups and nonpolar regions in between containing cationic alkyl side chains. During the heating process starting from 200 K, each system undergoes first a solid–solid phase transition at a lower temperature, and then a melting phase transition at a higher temperature to an isotropic liquid state (C₄, C₆, and C₈) or to a liquid crystal state (C₁₀ and C₁₂). After the solid–solid phase transition, all systems keep the triclinic space symmetry, but have a different set of lattice constants. C₄ has a more significant structural change in the nonpolar regions which narrows the layer spacing, while the layer spacings of other systems change little, which can be qualitatively understood by considering that the contribution of the effective van der Waals interaction in the nonpolar regions (abbreviated as EF1) to free energy becomes stronger with increasing side-chain length, and at the same time the contribution of the effective electrostatic interaction in the polar layers (abbreviated as EF2) to free energy remains almost the same. The melting phase transitions of all systems except C₆ are found to be a two-step process with an intermediate metastable state appeared during the melting from the crystal state to the liquid or liquid crystal state. Because the contribution of EF2 to the free energy is larger than EF1, the metastable state of C₄ has the feature of having higher ordered polar layers and lower ordered side-chain orientation. By contrast, C₈–C₁₂ have the feature of having lower ordered polar layers and higher ordered side-chain orientation, because for these systems, the contribution of EF2 to the free energy is smaller than EF1. No metastable state is found for C₆ because the free-energy contribution of EF1 is balanced with EF2

Concentration and Temperature Dependences of Polyglutamine Aggregation by Multiscale Coarse-Graining Molecular Dynamics Simulations

The solvent-free multiscale coarse-graining model of polyglutamine was employed to study polyglutamine aggregation at different concentrations and temperatures by means of molecular dynamics simulation. The heterogeneity order parameter (HOP) was used to quantify the polyglutamine aggregation. Our simulation results demonstrate that polyglutamine aggregation is sensitive to concentration and temperature changes. In equilibrium states, polyglutamine molecules fluctuate between aggregating tightly and distributing uniformly. The degree of aggregation monotonically increases with decreasing temperature, but the fluctuation of HOP reaches its maximum at an intermediate temperature. With increasing concentration, the distribution of polyglutamines first changes from more uniform to more nonuniform and then changes back to be more uniform, and the HOP has the widest distribution at the turning point. Simulations with different system sizes indicate that the finite-size effect is trivial and do not change the conclusions drawn for the polyglutamine system. In addition, the composition of the potential energies has been analyzed to confirm that the nonbonded interactions dominate the aggregation of polyglutamines. These results can be thermodynamically understood by considering the competition between the system entropy and molecular interactions, and a statistical model based on HOP has been developed to explain the microscopic mechanism of polyglutamine aggregation

Effect of Side-Chain Length on Structural and Dynamic Properties of Ionic Liquids with Hydroxyl Cationic Tails

The recent study has revealed that ionic liquids (ILs) with hydroxyl cationic tails are polar liquids without tightly aggregated nonpolar tail domains. Nevertheless, the influence of varying side-chain length on their microscopic structure and dynamics is still unclear. By performing all-atom molecular dynamics simulations for 1-(<i>n</i>-hydroxyalkyl)-3-methylimidazolium nitrate, where <i>n</i> varies from 2 to 12, we found that, with increasing side-chain length, both the nonpolar region and the flexibility of cationic tails increase. The larger nonpolar region pushes both the charged groups (heads and anions) and nonpolar groups (methylene groups on the side chains) to become more organized, while the increasing tail flexibility allows the hydroxyl terminals to retain a relatively uniform distribution. The increase of side-chain length does not apparently alter the polar nature of the ILs with hydroxyl tails, and has little effect on the total number of formed hydrogen bonds, but slows down the dynamics of ILs

Interplay between Intrinsic Conformational Propensities and Intermolecular Interactions in the Self-Assembly of Short Surfactant-like Peptides Composed of Leucine/Isoleucine

To study how the conformational propensities of individual amino acid residues, primary structures (i.e., adjacent residues and molecular lengths), and intermolecular interactions of peptides affect their self-assembly properties, we report the use of replica exchange molecular dynamics (REMD) to investigate the monomers, dimers, and trimers of a series of short surfactant-like peptides (I₃K, L₃K, L₄K, and L₅K). For four-residue peptides X₃K (I₃K and L₃K), the results show that their different aggregation behaviors arise from the different intrinsic conformational propensities of isoleucine and leucine. For L_<i>m</i>K peptides (L₃K, L₄K, and L₅K), the molecular length is found to dictate their aggregation via primarily modulating intermolecular interactions. Increasing the number of hydrophobic amino acid residues of L_<i>m</i>K peptides enhances their intermolecular H-bonding and promotes the formation of β-strands in dimer and trimer aggregates, overwhelming the intrinsic preference of Leu for helical structures. Thus, the interplay between the conformational propensities of individual amino acid residues for secondary structures and molecular interactions determines the self-assembly properties of the peptides, and the competition between intramolecular and intermolecular H-bonding interactions determines the probability of β-sheet alignment of peptide molecules. These results are validated by comparing simulated and experimental CD spectra of the peptides. This study will aid the design of short peptide amphiphiles and improve the mechanistic understanding of their self-assembly behavior

Cultured cells from <i>CathA</i>^<i>S190A</i><i>/Scpep1</i>^<i>-/-</i> mice show significantly increased proliferation response to ET-1.

<p>Primary cultures of corneal epithelial cells (CEC) (<b>A, B</b>), skin fibroblasts <b>(C, D, E, F)</b> and ASMC (<b>G, J</b> and <b>K</b>) were established by proteolytic digestion of combined corneas, skin tissues and aortas, respectively, extracted from 4 week-old mice of similar sex and genotype. CEC (<b>A</b>) and skin fibroblasts (<b>C, D</b>) and ASMC (<b>G</b>) were seeded into 96-well plates at a density of 1×10⁵ cells per well and incubated at 37°C for 24 h, serum-starved overnight and treated with 100 nM ET-1. After 24 h the concentration of cells was measured by MTT assay (<b>A</b>, <b>C, G</b>) or cell counting (<b>D</b>). The rate of DNA synthesis by fibroblasts (<b>E</b>) and ASMC (<b>J</b>) in the presence of 100 nM ET-1 was evaluated by incorporation of [³H] thymidine. The fraction of cells expressing proliferation markers Ki-67 (<b>B, K</b>) and PCNA (<b>F</b>) in the serum-free medium <b>(Ctrl.),</b> in the presence of 100 nM ET-1 <b>(ET-1)</b> or in complete medium (<b>C.M.</b>) was analyzed by immunocytochemistry. The panel shows a representative image of skin fibroblasts from <i>WT</i> and <i>CathA</i>^<i>S190A</i>/<i>Scpep1</i>^<i>-/-</i> mice untreated (<b>Ctrl.</b>) or treated with 100 nM ET-1 (<b>ET-1</b>) and stained with antibodies against PCNA (green) and propidium iodide (red). Bar graphs show (%) of PCNA or Ki67-positive cells measured using ImageJ software. Values are shown as means (±S.E) of at least 3 independent experiments. Two-way repeated measurements ANOVA was used to test differences between the genotypes: significant differences between the mean values in Bonferroni post-test (* <i>p</i><0.05, ** <i>p</i><0.001, *** <i>p</i><0.0001) are shown.</p

Increased AKT phosphorylation in ET-1-treated cultured skin fibroblasts from CathA^S190A/Scpep1^-/- mice.

<p><b>(A)</b> Increased AKT phosphorylation in fibroblasts from CathA/Scpep1-deficient mice. Cultured fibroblasts from WT, <i>Scpep1</i>^<i>-/-</i>, <i>CathA</i>^<i>S190A</i> and <i>CathA</i>^<i>S190A</i><i>/Scpep1</i>^<i>-/-</i> mice were treated for 5 min with 100 nM ET-1. Total protein extracts were analyzed by Western blotting using antibodies specific for phosphorylated (pAKT) and total AKT protein (tAKT). <b>(B)</b> Pharmacological antagonists of ET receptors, BQ610 and BQ788 reduce AKT phosphorylation in cultured mouse fibroblasts treated with ET-1. Cultured fibroblasts from WT mice were treated or not for 30 min with 2 μM BQ610 or BQ788 followed by 5 min induction with 100 nM ET-1 as indicated on the figure. Total protein extracts were analyzed by Western blotting using antibodies specific for phosphorylated (pAKT) and total AKT protein. Panels show representative data of 3 independent experiments. Graphs below the panels shows ratios (mean values and S.D.) of signal intensities for phosphorylated and total AKT protein measured using Image J software. * <i>p</i><0.05 in paired two-tailed <i>t</i>-test.</p

ETA receptor antagonist, BQ610, ETB receptor antagonist, BQ788 and MEK1/2 kinase antagonists, U0126 and PD98059 block both the proliferative effect of 100 nM ET-1 and ERK1/2 phosphorylation.

<p>Pharmacological antagonists of ET receptors, BQ610 and BQ788 (<b>A</b>) and MEK1/2 kinase antagonists, U0126 and PD98059 (<b>B</b>) reduce ERK1/2 phosphorylation in cultured mouse fibroblasts treated with ET-1. In ASMC ERK1/2 phosphorylation was partially reduced by ETR-A antagonist BQ610 (<b>D</b>) and significantly inhibited by MEK1/2 kinase antagonists, U0126 and PD98059 (<b>E</b>). Serum-starved cultured fibroblasts and ASMC from WT mice were treated or not for 30 min with 2 μM BQ610 and BQ788 or with 10 μM U0126 and 25 μM PD98059 followed by 5 min induction with 100 nM ET-1 as indicated on the figure. Total protein extracts were analyzed by Western blotting using antibodies specific for phosphorylated (pThr²⁰²/Thr²⁰⁴-ERK1/2) and total ERK1/2 protein. Panel shows representative data of 3 independent experiments. Bar graphs show ratios (means and S.D.) of signal intensities for phosphorylated and total ERK1/2 estimated with ImageJ software. * <i>p</i><0.05 in paired two-tailed <i>t</i>-test. (<b>C, F</b>) Inhibitors of MEK1/2 kinase, U0126 and PD98059 block ET-1 induced proliferation of skin fibroblasts. Cultured fibroblasts from WT mice were serum-starved overnight and treated for 24 h with 100 nM ET-1 in the medium containing 1% FBS in the presence or absence of 2 μM BQ610 or BQ788 as indicated on the figure. Cell proliferation was measured by incorporation of [³H] thymidine (<b>C</b>) and MTT assay (<b>F</b>) as described in the Materials and Methods.</p

Increased ERK1/2 phosphorylation in ET-1-treated cultured skin fibroblasts and ASMC from <i>CathA</i>^<i>S190A</i><i>/Scpep1</i>^<i>-/-</i> mice.

<p>Cultured mouse fibroblasts <b>(A</b>) and ASMC <b>(B)</b> were serum-starved and treated with 100 mM ET-1 for 0–60 min as indicated on the figure. Total protein extracts were analyzed by Western blotting using antibodies specific to ERK1/2 phosphorylated at Thr202 and Tyr204 residues (pERK1/2) and total ERK1/2 protein (tERK1/2). <b>(C, D)</b> Increased ERK1/2 phosphorylation in fibroblasts and ASMC from Scpep1/CathA-deficient mice. Cultured fibroblasts <b>(C)</b> and ASMC <b>(D)</b> from WT, <i>Scpep1</i>^<i>-/-</i>, <i>CathA</i>^<i>S190A</i> and <i>CathA</i>^<i>S190A</i><i>/Scpep1</i>^<i>-/-</i> mice were treated for 5 min with 100 nM ET-1. Total protein extracts were analyzed by Western blotting using antibodies specific for phosphorylated and total ERK1/2 protein. Panels show representative data of 3 independent experiments. Bar graphs show ratios (means and S.D.) of signal intensities for phosphorylated and total ERK1/2 measured using ImageJ software. * <i>p</i><0.05 in paired two-tailed <i>t</i>-test.</p

Representative images of transversal sections of abdominal skin fragments derived from WT 6 month-old mouse and age-matched counterparts with indicated selective or combined CathA/Scpep1 deficiencies.

<p>Sections are stained with the pentachrome Movat’s method that visualized back elastin, yellowish collagen and greenish proteoglycans. Mice, either with the single or double deficiencies of <i>CathA</i>^<i>S190A</i> <i>and Scpep1</i>^<i>-/-</i> have thicker skin that contains enlarged hyperplastic epidermal glands as well as more extracellular collagen Type I and elastin as compared with their WT counterparts (arrows) suggesting the dermal hypertrophy. Tissues of all tested knockout mice also demonstrate remarkable reduction of dermal fat (arrowheads). Scale bar equals 100 μm.</p