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We develop a Stockmayer fluid model that accounts for the dielectric responses of polar solvents (water, MeOH, EtOH, acetone, 1-propanol, DMSO, and DMF) and NaCl solutions. These solvent molecules are represented by Lennard-Jones (LJ) spheres with permanent dipole moments and the ions by charged LJ spheres. The simulated dielectric constants of these liquids are comparable to experimental values, including the substantial decrease in the dielectric constant of water upon the addition of NaCl. Moreover, the simulations predict an increase in the dielectric constant when considering the influence of ion translations in addition to the orientation of permanent dipoles. [ABSTRACT FROM AUTHOR]

Cation conducting channelrhodopsins (ChRs) are a popular tool used in optogenetics to control the activity of excitable cells and tissues using light. ChRs with altered ion selectivity are in high demand for use in different cell types and for other specialized applications. However, a detailed mechanism of ion permeation in ChRs is not fully resolved. Here, we use complementary experimental and computational methods to uncover the mechanisms of cation transport and valence selectivity through the channelrhodopsin chimera, C1C2, in the high- and low-conducting open states. Electrophysiology measurements identified a single-residue substitution within the central gate, N297D, that increased Ca2+ permeability vs. Na+ by nearly two-fold at peak current, but less so at stationary current. We then developed molecular models of dimeric wild-type C1C2 and N297D mutant channels in both open states and calculated the PMF profiles for Na+ and Ca2+ permeation through each protein using well-tempered/multiple-walker metadynamics. Results of these studies agree well with experimental measurements and demonstrate that the pore entrance on the extracellular side differs from original predictions and is actually located in a gap between helices I and II. Cation transport occurs via a relay mechanism where cations are passed between flexible carboxylate sidechains lining the full length of the pore by sidechain swinging, like a monkey swinging on vines. In the mutant channel, residue D297 enhances Ca2+ permeability by mediating the handoff between the central and cytosolic binding sites via direct coordination and sidechain swinging. We also found that altered cation binding affinities at both the extracellular entrance and central binding sites underly the distinct transport properties of the low-conducting open state. This work significantly advances our understanding of ion selectivity and permeation in cation channelrhodopsins and provides the insights needed for successful development of new ion-selective optogenetic tools. [ABSTRACT FROM AUTHOR]

In potassium channels that conduct K+ selectively over Na+, which sites are occupied by K+ or water and the mechanism of selectivity are unresolved questions. The combination of the energetics and the constraints imposed by the protein structure yield the selective permeation and occupancy. To gain insight into the combination of structure and energetics, we performed density functional theory (DFT) calculations of multiple N-methyl acetamide (NMA) ligands binding to K+ and Na+, relative to hydrated K+ and Na+. NMA is an analogue of the amino acid backbone and provides the carbonyl binding to the ions that occurs in most binding sites of the K+ channel. Unconstrained optimal structures are obtained through geometry optimization calculations of the NMA ligand binding. The complexes formed by 8 NMA binding to the cations have the O atoms positioned in nearly identical locations as the O atoms in the selectivity filter. The transfer free energies between bulk water and K+ or Na+ bound to 8 NMA are almost identical, implying there is no selectivity by a single site. For water optimized with 8 NMA, binding is weak and O atoms are not positioned as in the K+ channel selectivity filter, suggesting that the ions are much more favored than water. Optimal structures of 8 NMA binding with two cations (K+ or Na+) are stable and have lower binding free energy than the optimal structures with just one cation. However, in the Na+ case, the optimal structure deforms and does not match the K+ channel; that is, two bound Na+ are destabilizing. In contrast, the two K+ structure is stabilized and the selectivity free energy favors K+. Overall, this study shows that binding site occupancy and the mechanism for K+ selectivity involves multiple K+ binding in multiple neighboring layers or sites of the K+ channel selectivity filter. [ABSTRACT FROM AUTHOR]

Polymerization induced phase separation (PIPS) in a three component thermoset is studied using molecular dynamics simulations of a new coarse-grained thermoset model. The system includes two crosslinker molecules, which differ in their glass transition temperatures (Tg) and chain length and thus have the potential for phase separation. One crosslinker has a high Tg corresponding to a rubbery behavior, and simulations were performed for a short length (4 beads) and a long length (33 beads). The resin and other crosslinker have low Tg. A coarse-grained model is developed with these features and with interaction parameters determined so that for either rubbery crosslinker length, the system is in the liquid state at the cure temperature. For sufficiently slow reaction rates, the long rubbery molecule exhibits PIPS into a bicontinuous array of nanoscale domains, but the short one does not, reproducing recent experimental results. The simulations demonstrate that the reaction rates must be slow enough to allow diffusion to yield phase separation. Particularly, the reaction rate corresponding to the secondary amine must be very slow, else the structure of crosslinked clusters and the substantially increased diffusion time will prevent PIPS. [ABSTRACT FROM AUTHOR]

The interactions of carboxylate anions with water and cations are important for a wide variety of systems, both biological and synthetic. To gain insight on properties of the local complexes, we apply density functional theory, to treat the complex electrostatic interactions, and investigate mixtures with varied numbers of carboxylate anions (acetate) and waters binding to monovalent cations, Li+, Na+ and K+. The optimal structure with overall lowest free energy contains two acetates and two waters such that the cation is four-fold coordinated, similar to structures found earlier for pure water or pure carboxylate ligands. More generally, the complexes with two acetates have the lowest free energy. In transitioning from the overall optimal state, exchanging an acetate for water has a lower free energy barrier than exchanging water for an acetate. In most cases, the carboxylates are monodentate and in the first solvation shell. As water is added to the system, hydrogen bonding between waters and carboxylate O atoms further stabilizes monodentate structures. These structures, which have strong electrostatic interactions that involve hydrogen bonds of varying strength, are significantly polarized, with ChelpG partial charges that vary substantially as the bonding geometry varies. Overall, these results emphasize the increasing importance of water as a component of binding sites as the number of ligands increases, thus affecting the preferential solvation of specific metal ions and clarifying Hofmeister effects. Finally, structural analysis correlated with free energy analysis supports the idea that binding to more than the preferred number of carboxylates under architectural constraints are a key to ion transport. [ABSTRACT FROM AUTHOR]

Very large molecular dynamics simulations with open ends between two solid adherends have been performed treating tensile deformation of coarse-grained, highly crosslinked polymer networks modeling epoxy systems. The open boundary and the presence of corners dramatically alter the fracture behavior. In contrast to systems with periodic boundaries, the failure strain decreases with increasing system size until a critical size is reached. This decrease greatly reduces the difference in the crack initiation strains between simulation and experiment. In the open geometry, the sides of the polymer network contract inward forming wedge shaped corners. The stress and strain are concentrated in the corners where the shear component is present and large. The nonuniformity of the strain results in accumulation of bond breaking in the corners and crack initiation there. Moreover, the corner strain is system size dependent, which results in a system size dependence of the failure strain. [ABSTRACT FROM AUTHOR]

We present simulations of the force-extension curves of strong polyelectrolytes with varying intrinsic stiffness as well as specifically treating hyaluronic acid, a polyelectrolyte of intermediate stiffness. Whereas fully flexible polyelectrolytes show a high-force regime where extension increases nearly logarithmically with force, we find that the addition of even a small amount of stiffness alters the short-range structure and removes this logarithmic elastic regime. This further confirms that the logarithmic regime is a consequence of the short-ranged "wrinkles" in the flexible chain. As the stiffness increases, the force-extension curves tend toward and reach the wormlike chain behavior. Using the screened Coulomb potential and a simple bead-spring model, the simulations are able to reproduce the hyaluronic acid experimental force-extension curves for salt concentrations ranging from 1 to 500 mM. Furthermore, the simulation data can be scaled to a universal curve like the experimental data. The scaling analysis is consistent with the interpretation that, in the low-salt limit, the hyaluronic acid chain stiffness scales with salt with an exponent of −0.7, rather than either of the two main theoretical predictions of −0.5 and −1. Furthermore, given the conditions of the simulation, we conclude that this exponent value is not due to counterion condensation effects, as had previously been suggested. [ABSTRACT FROM AUTHOR]

Almost all studies of specific ion binding by carboxylates (–COO−) have considered only a single cation, but clustering of ions and ligands is a common phenomenon. We apply density functional theory to investigate how variations in the number of acetate ligands in binding to two monovalent cations affects ion binding preferences. We study a series of monovalent (Li+, Na+, K+, Cs+) ions relevant to experimental work on many topics, including ion channels, battery storage, water purification and solar cells. We find that the preferred optimal structure has 3 acetates except for Cs+, which has 2 acetates. The optimal coordination of the cation by the carboxylate O atoms is 4 for both Na+ and K+, and 3 for Li+ and Cs+. There is a 4-fold coordination minimum just a few kcal mol−1 higher than the optimal 3-fold structure for Li+. For two cations, multiple minima occur in the vicinity of the lowest free energy state. We find that, for Li, Na and K, the preferred optimal structure with two cations is favored over a mixture of single cation complexes, providing a basis for understanding ionic cluster formation that is relevant for engineering proteins and other materials for rapid, selective ion transport. [ABSTRACT FROM AUTHOR]

Ordering nanoparticles into a desired super-structure is often crucial for their technological applications. We use molecular dynamics simulations to study the assembly of nanoparticles in a polymer brush randomly grafted to a planar surface as the solvent evaporates. Initially, the nanoparticles are dispersed in a solvent that wets the polymer brush. After the solvent evaporates, the nanoparticles are either inside the brush or adsorbed at the surface of the brush, depending on the strength of the nanoparticle-polymer interaction. For strong nanoparticle-polymer interactions, a 2-dimensional ordered array is only formed when the brush density is finely tuned to accommodate a single layer of nanoparticles. When the brush density is higher or lower than this optimal value, the distribution of nanoparticles shows large fluctuations in space and the packing order diminishes. For weak nanoparticle-polymer interactions, the nanoparticles order into a hexagonal array on top of the polymer brush as long as the grafting density is high enough to yield a dense brush. An interesting healing effect is observed for a low-grafting-density polymer brush that can become more uniform in the presence of weakly adsorbed nanoparticles. [ABSTRACT FROM AUTHOR]

Nanofabrication using arrays of modified atomic force microscopy (AFM) tips can drastically reduce feature sizes and increase data storage densities. Additionally, AFM experiments are valuable tools for characterizing the tribological properties of surfaces. In order to maxim&e the potential of nanofabrication techniques, it is necessary to understand fully the interactions between AFM tips and substrates, particularly when the latter is compliant and more damage-prone. To address this issue, we have carried out extensive molecular dynamics simulations of the nanotribological properties of self-assembled alkylsilane monolayers (SAMs) on amorphous silica with a realistic model of an AFM tip. Our simulations demonstrate that for fully physisorbed SAMs, even low load contacts can damage the SAM and cause material transfer to the probe tip. This effect, which is commonly ignored, can have a strong effect on the interpretation of experimental measurements. Partial chemisorption of the SAM lowers, but does not remove the possibility of damage. [DOI: 10.1115/1.4001660]

Young's elastic modulus and the persistence length are calculated for a coarse-grained model of tubule forming polymers. The model uses a wedge shaped composite of particles that previously has been shown to self-assemble into tubules. These calculations demonstrate that the model yields very large persistence lengths (corresponding to 78-126 μm) that are comparable to that observed in experiments for the microtubule lengths accessible to the calculations. The source for the stiffness is the restricted rotation of the monomer due to the excluded volume interactions between bonded macromolecular monomers as well as the binding between monomers. For this reason, large persistence lengths are common in tubule systems with a macromolecule as the monomer. The persistence length increases linearly with increased binding strength in the filament direction. No dependence in the persistence length is found for varying the tubule pitch for geometries with the protofilaments remaining straight. [ABSTRACT FROM AUTHOR]

We perform molecular dynamics simulations of a coarse-grained model of ionomer melts in an applied oscillating electric field. The frequency-dependent conductivity and susceptibility are calculated directly from the current density and polarization density, respectively. At high frequencies, we find a peak in the real part of the conductivity due to plasma oscillations of the ions. At lower frequencies, the dynamic response of the ionomers depends on the ionic aggregate morphology in the system, which consists of either percolated or isolated aggregates. We show that the dynamic response of the model ionomers to the applied oscillating field can be understood by comparison with relevant time scales in the systems, obtained from independent calculations. [ABSTRACT FROM AUTHOR]

A coarse-grained (CG) model is developed for the thermoresponsive polymer poly(Nisopropylacrylamide) (PNIPAM), using a hybrid top-down and bottom-up approach. Nonbonded parameters are fit to experimental thermodynamic data following the procedures of the SDK (Shinoda, DeVane, and Klein) CG force field, with minor adjustments to provide better agreement with radial distribution functions from atomistic simulations. Bonded parameters are fit to probability distributions from atomistic simulations using multi-centered Gaussian-based potentials. The temperature-dependent potentials derived for the PNIPAM CG model in this work properly capture the coil-globule transition of PNIPAM single chains and yield a chain-length dependence consistent with atomistic simulations. [ABSTRACT FROM AUTHOR]

Rationale: Chronic airway infection and inflammation resulting in progressive, obstructive lung disease is the leading cause of morbidity and mortality in cystic fibrosis. Understanding the lower airway microbiota across the ages can provide valuable insight and potential therapeutic targets. Objectives: To characterize and compare the lower airway microbiota in cystic fibrosis and disease control subjects across the pediatric age spectrum. Methods: Bronchoalveolar lavage fluid samples from 191 subjects (63 with cystic fibrosis) aged 0 to 21 years were collected along with relevant clinical data. We measured total bacterial load using quantitative polymerase chain reaction and performed 16S rRNA gene sequencing to characterize bacterial communities with species-level sensitivity for select genera. Clinical comparisons were investigated. Measurements and main results: Cystic fibrosis samples had higher total bacterial load and lower microbial diversity, with a divergence from disease controls around 2–5 years of age, as well as higher neutrophilic inflammation relative to bacterial burden. Cystic fibrosis samples had increased abundance of traditional cystic fibrosis pathogens and decreased abundance of the Streptococcus mitis species group in older subjects. Interestingly, increased diversity in the heterogeneous disease controls was independent of diagnosis and indication. Sequencing was more sensitive than culture, and antibiotic exposure was more common in disease controls, which showed a negative relationship with load and neutrophilic inflammation. Conclusions: Analysis of lower airway samples from people with cystic fibrosis and disease controls across the ages revealed key differences in airway microbiota and inflammation. The divergence in subjects during early childhood may represent a window of opportunity for intervention and additional study. [ABSTRACT FROM AUTHOR]

We perform atomistic molecular dynamics simulations of melts of four precise acid copolymers, two poly(ethylene-co-acrylic acid) (PEAA) copolymers, and two poly(ethylene-co-sulfonic acid) (PESA) copolymers. The acid groups are spaced by either 9 or 21 carbons along the polymer backbones. Hydrogen bonding causes the acid groups to form aggregates. These aggregates give rise to a low wavevector peak in the structure factors, in agreement with X-ray scattering data for the PEAA materials. The structure factors for the PESA copolymers are very similar to those for the PEAA copolymers, indicating a similar distance between aggregates which depends on the spacer length but not on the nature of the acid group. The PEAA copolymers are found to form more dimers and other small aggregates than do the PESA copolymers, while the PESA copolymers have both more free acid groups and more large aggregates. [ABSTRACT FROM AUTHOR]