Interfacial interactions of glutamate, water and ions with carbon nanopore evaluated by molecular dynamics simulations

Molecular dynamics simulations were used to assess the transport of glutamate, water and ions (Na⁺ and Cl⁻) in a single wall carbon nanopore. The spatial profiles of Na⁺ and Cl⁻ ions are largely determined by the pore wall charges. Co-ions are repelled whereas the counter-ions are attracted by the pore charges, but this ‘rule’ breaks down when the water concentration is set to a level significantly below that in the physiological bulk solution. In such cases water is less able to counteract the ion-wall interactions (electrostatic or non-electrostatic), co-ions are layered near the counter-ions attracted by the wall charges and are thus layered as counter-ions. Glutamate is concentrated near the pore wall even at physiological water concentration, and irrespective of whether the pore wall is neutral or charged (positively or negatively), and its peak levels are up to 40 times above mean values. The glutamate is thus always layered as a counter-ion. Layering of water near the wall is independent of charges on the pore wall, but its peak levels near the wall are ‘only’ 6-8 times above the pore mean values. However, if the mean concentration of water is significantly below the level in the physiological bulk solution, its layering is enhanced, whereas its concentration in the pore center diminishes to very low levels. Reasons for such a ‘paradoxical’ behavior of molecules (glutamate and water) are that the non-electrostatic interactions are (except at very short distances) attractive, and electrostatic interactions (between the charged atoms of the glutamate or water and the pore wall) are also attractive overall. Repulsive interactions (between equally charged atoms) exist, and they order the molecules near the wall, whereas in the pore center the glutamate (and water) angles are largely randomly distributed, except in the presence of an external electric field. Diffusion of molecules and ions is complex. The translational diffusion is in general both inhomogeneous and anisotropic. Non-electrostatic interactions (ion-wall, glutamate-wall or water-wall) powerfully influence diffusion. In the neutral nanopore the effective axial diffusion constants of glutamate, water and Na⁺ and Cl⁻ ions are all < 10% of their values in the bulk, and the electrostatic interactions can reduce them further. Diffusion of molecules and ions is further reduced if the water concentration in the pore is low. Glutamate⁻ is slowed more than water, and ions are reduced the most especially co-ions. In conclusion the interfacial interactions influence the spatial distribution of glutamate, water and ions, and regulate powerfully, in a complex manner and over a very wide range their transport through nanosize pores.     

Glutamate, water and ion transport through a charged nanosize pore

The transport of transmitter, ions and water through a positively-charged nanopore was investigated through computer simulations. The physics of the problem is described by a coupled set of Poisson-Nernst-Planck and Navier-Stokes equations in a computational domain consisting a cylindrical pore, whose radius ranged from 1 to 8 nm and which was flanked by two compartments representing the vesicular interior and extra-cellular space. The concentration of co-ions is suppressed and of counter-ions enhanced, especially near the pore wall owing to electrostatic interactions. Glutamate (i.e. the transmitter considered) is negatively charged and is simulated as a counter-ion. The electro-kinetically induced pressure due to the movement of ions is negative and very pronounced near the pore wall where the concentration and flux of counter-ions is very high. The water velocity peaks in the pore center, diminishes to zero at the pore wall, but is constant along the pore axis. The mean velocity of the water/fluid is proportional to the vesicular pressure and pore cross-sectional area. Interestingly it is inversely related to the vesicular glutamate concentration. The factors determining the glutamate flux are complex. The diffusive flux generally predominates for narrow pore, and convective flux may dominate for wide pore if the vesicular pressure is high. Surprisingly at low vesicular pressure the mean total glutamate flux per unit cross-sectional pore area is higher for narrow pores. Higher flux is probably due to the rise of glutamate concentration in the nanopore, which is much more pronounced for narrow nanopores, due to the maintenance of approximate neutrality of charges in the pore and on the pore wall. In conclusion intra-vesicular pressure helps 'flushing-out' the transmitter, but the induced pressure 'drags-out' the water into the extra-cellular space.     

Glutamate, water and ion transport through a charged nanosize pore

The transport of transmitter, ions and water through a positively-charged nanopore was investigated through computer simulations. The physics of the problem is described by a coupled set of Poisson-Nernst-Planck and Navier-Stokes equations in a computational domain consisting a cylindrical pore, whose radius ranged from 1 to 8 nm and which was flanked by two compartments representing the vesicular interior and extra-cellular space. The concentration of co-ions is suppressed and of counter-ions enhanced, especially near the pore wall owing to electrostatic interactions. Glutamate (i.e. the transmitter considered) is negatively charged and is simulated as a counter-ion. The electro-kinetically induced pressure due to the movement of ions is negative and very pronounced near the pore wall where the concentration and flux of counter-ions is very high. The water velocity peaks in the pore center, diminishes to zero at the pore wall, but is constant along the pore axis. The mean velocity of the water/fluid is proportional to the vesicular pressure and pore cross-sectional area. Interestingly it is inversely related to the vesicular glutamate concentration. The factors determining the glutamate flux are complex. The diffusive flux generally predominates for narrow pore, and convective flux may dominate for wide pore if the vesicular pressure is high. Surprisingly at low vesicular pressure the mean total glutamate flux per unit cross-sectional pore area is higher for narrow pores. Higher flux is probably due to the rise of glutamate concentration in the nanopore, which is much more pronounced for narrow nanopores, due to the maintenance of approximate neutrality of charges in the pore and on the pore wall. In conclusion intra-vesicular pressure helps ‘flushing-out’ the transmitter, but the induced pressure ‘drags-out’ the water into the extra-cellular space.     

Positive charges at the intracellular mouth of the pore regulate anion conduction in the CFTR chloride channel

Many different ion channel pores are thought to have charged amino acid residues clustered around their entrances. The so-called surface charges contributed by these residues can play important roles in attracting oppositely charged ions from the bulk solution on one side of the membrane, increasing effective local counterion concentration and favoring rapid ion movement through the channel. Here we use site-directed mutagenesis to identify arginine residues contributing important surface charges in the intracellular mouth of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel pore. While wild-type CFTR was associated with a linear current-voltage relationship with symmetrical solutions, strong outward rectification was observed after mutagenesis of two arginine residues (R303 and R352) located near the intracellular ends of the fifth and sixth transmembrane regions. Current rectification was dependent on the charge present at these positions, consistent with an electrostatic effect. Furthermore, mutagenesis-induced rectification was more pronounced at lower Cl(-) concentrations, suggesting that these mutants had a reduced ability to concentrate Cl(-) ions near the inner pore mouth. R303 and R352 mutants exhibited reduced single channel conductance, especially at negative membrane potentials, that was dependent on the charge of the amino acid residue present at these positions. However, the very low conductance of both R303E and R352E-CFTR could be greatly increased by elevating intracellular Cl(-) concentration. Modification of an introduced cysteine residue at position 303 by charged methanethiosulfonate reagents reproduced charge-dependent effects on current rectification. Mutagenesis of arginine residues in the second and tenth transmembrane regions also altered channel permeation properties, however these effects were not consistent with changes in channel surface charges. These results suggest that positively charged arginine residues act to concentrate Cl(-) ions at the inner mouth of the CFTR pore, and that this contributes to maximization of the rate of Cl(-) ion permeation through the pore.     

Why forces between proteins follow different Hofmeister series for pH above and below pI

The relative effectiveness of different anions in crystallizing proteins follows a reversed Hofmeister sequence for pHpI. The phenomenon has been known almost since Hofmeister's original work but it has not been understood. It is here given a theoretical explanation. Classical electrolyte and double layer theory deals only with electrostatic forces acting between ions and proteins. Hydration and hydration interactions are dealt with usually only in terms of assumed hard core models. But there are, at and above biological salt concentrations, other non-electrostatic (NES) ion-specific forces acting that are ignored in such modeling. Such electrodynamic fluctuation forces are also responsible for ion-specific hydration. These missing forces are variously comprehended under familiar but generally unquantified terms, typically, hydration, hydrogen bonding, pi-electron-cation interactions, dipole-dipole, dipole-induced dipole and induced dipole-induced dipole forces and so on. The many important body electrodynamic fluctuation force contributions are accessible from extensions of Lifshitz theory from which, with relevant dielectric susceptibility data on solutions as a function of frequency, the forces can be extracted quantitatively, at least in principle. The classical theories of colloid science that miss such contributions do not account for a whole variety of ion-specific phenomena. Numerical results that include these non-electrostatic forces are given here for model calculations of the force between two model charge-regulated hen-egg-white protein surfaces. The surfaces are chosen to carry the same charge groups and charge density as the protein. What emerges is that for pHpI (where anions are co-ions) the forces increase in the order NaCl相似文献   

Extrusion of transmitter, water and ions generates forces to close fusion pore

During exocytosis the fusion pore opens rapidly, then dilates gradually, and may subsequently close completely, but what controls its dynamics is not well understood. In this study we focus our attention on forces acting on the pore wall, and which are generated solely by the passage of transmitter, ions and water through the open fusion pore. The transport through the charged cylindrical nano-size pore is simulated using a coupled system of Poisson-Nernst-Planck and Navier-Stokes equations and the forces that act radially on the wall of the fusion pore are then estimated. Four forces are considered: a) inertial force, b) pressure, c) viscotic force, and d) electrostatic force. The inertial and viscotic forces are small, but the electrostatic force and the pressure are typically significant. High vesicular pressure tends to open the fusion pore, but the pressure induced by the transport of charged particles (glutamate, ions), which is predominant when the pore wall charge density is high tends to close the pore. The electrostatic force, which also depends on the charge density on the pore wall, is weakly repulsive before the pore dilates, but becomes attractive and pronounced as the pore dilates. Given that the vesicular concentration of free transmitter can change rapidly due to the release, or owing to the dissociation from the gel matrix, we evaluated how much and how rapidly a change of the vesicular K⁺-glutamate⁻ concentration affects the concentration of glutamate⁻ and ions in the pore and how such changes alter the radial force on the wall of the fusion pore. A step-like rise of the vesicular K⁺-glutamate⁻ concentration leads to a chain of events. Pore concentration (and efflux) of both K⁺ and glutamate⁻ rise reaching their new steady-state values in less than 100 ns. Interestingly within a similar time interval the pore concentration of Na⁺ also rises, whereas that of Cl⁻ diminishes, although their extra-cellular concentration does not change. Finally such changes affect also the water movement. Water efflux changes bi-phasically, first increasing before decreasing to a new, but lower steady-state value. Nevertheless, even under such conditions an overall approximate neutrality of the pore is maintained remarkably well, and the electrostatic, but also inertial, viscotic and pressure forces acting on the pore wall remain constant. In conclusion the extrusion of the vesicular content generates forces, primarily the force due to the electro-kinetically induced pressure and electrostatic force (both influenced by the pore radius and even more by the charge density on the pore wall), which tend to close the fusion pore.     

Bi-ionic potentials of bovine lens capsules and collodion membranes

Concentration dependencies of bi-ionic potentials of well-cleaned bovine lens capsules in vitro, of collodion and of modified collodion membranes were studied. The lens capsules have positively fixed charges, and collodion membranes have negatively fixed charges. As these membranes are partially selectively permeable, both co-ions and counter-ions exist in the membrane. However, many studies on bi-ionic potentials have been limited to systems in which the membrane has extreme ionic selectivity and co-ions are completely excluded from the membrane. Experimental results agreed with theoretical values obtained by assuming the common ion concentration to be constant throughout the membrane for systems such as KCl(C)-membrane (θ>0, or θ<0)-NaCl(C), NaNO₃(C)-membrane (θ>0)-NaCl(C) and CaCl₂(C₁)-membrane (θ>0)-NaCl(C₂) (C₂/C₁ = 2), where C is the bulk concentration. The theoretical reliability of this assumption was checked. When both electrolytes in solution were uni-univalent, the ratio of ionic mobilities of two counter-ions (or two co-ions) in all of these membranes was almost the same as the ratio obtained in bulk solution, while the ratio of ionic mobilities of the counter-ion and the co-ion was almost the same as the ratio obtained in bulk solution for the lens capsule, but different in the case of the collodion and modified collodion membranes.     

Monte Carlo simulation of the water in a channel with charges.

A Monte Carlo simulation of water in a channel with charges suggests the existence of water in immobile, high density, essentially glasslike form near the charges. The channel model has a conical section with an opening through which water molecules can pass, at the narrow end of the cone, and a cylindrical section at the other end. When the charges are placed near the narrow section of the model, the "glass" effectively blocks the channel; with the charges removed, the channel opens. The effect can be determined from the rate of passage of the water molecules through the pore, from the average orientation of the water molecule, and from distortion of the distribution of molecules. In the simulations carried out to date, no external ions have been considered. In addition to the energy, the Helmholtz free energy has been calculated.     

Elastic, electrostatic and electrokinetic forces influencing membrane curvature

Many cellular and intracellular processes critically depend on membrane shape, but the shape generating mechanisms are still to be fully understood. In this study we evaluate how electrostatic/electrokinetic forces contribute to membrane curvature. Membrane bilayer had finite thickness and was either elastically anisotropic or anisotropic overall, but isotropic per sections (heads and tails). The physics of the situation was evaluated using a coupled system of elastic and electrostatic/electrokinetic (Poisson-Nernst-Planck) equations. The fixed charges present only on the upper membrane surface lead to the accumulation of counter-ions and depletion of co-ions that decay spatially very rapidly (Debye length<1nm), as does the potential and electric field. Spatially uneven electric field and the permittivity mismatch also induce charges at the membrane-solution interface, which are not fixed but influence the electrostatics nevertheless. Membrane bends due to - Coulomb force (caused by fixed membrane charges in the electric field) and the dielectric force (due to the non-uniform electric field and the permittivity mismatch between the membrane and the solution). Both act as membrane surface forces, and both depend supra-linearly on the fixed charge density. Regardless of sign of the fixed charges, the membrane bends toward the charged (upper) surface owing to the action of the Coulomb force, but this is opposed by the smaller dielectric force. The spontaneous membrane curvature becomes very pronounced at high fixed charge densities, leading to very small spontaneous radii (<50nm). In conclusion the electrostatic/electrokinetic forces contribute significantly to the membrane curvature.     

Metal ion effects on ion channel gating

Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated on channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-à-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.     

The pore helix dipole has a minor role in inward rectifier channel function

Ion channels lower the energetic barrier for ion passage across cell membranes and enable the generation of bioelectricity. Electrostatic interactions between permeant ions and channel pore helix dipoles have been proposed as a general mechanism for facilitating ion passage. Here, using genetic selections to probe interactions of an exemplar potassium channel blocker, barium, with the inward rectifier Kir2.1, we identify mutants bearing positively charged residues in the potassium channel signature sequence at the pore helix C terminus. We show that these channels are functional, selective, resistant to barium block, and have minimally altered conductance properties. Both the experimental data and model calculations indicate that barium resistance originates from electrostatics. We demonstrate that potassium channel function is remarkably unperturbed when positive charges occur near the permeant ions at a location that should counteract pore helix electrostatic effects. Thus, contrary to accepted models, the pore helix dipole seems to be a minor factor in potassium channel permeation.     

Structural basis for ion conduction and gating in ClC chloride channels

Members of the ClC family of voltage-gated chloride channels are found from bacteria to mammals with a considerable degree of conservation in the membrane-inserted, pore-forming region. The crystal structures of the ClC channels of Escherichia coli and Salmonella typhimurium provide a structural framework for the entire family. The ClC channels are homodimeric proteins with an overall rhombus-like shape. Each ClC dimer has two pores each contained within a single subunit. The ClC subunit consists of two roughly repeated halves that span the membrane with opposite orientations. This antiparallel architecture defines a chloride selectivity filter within the 15-A neck of a hourglass-shaped pore. Three Cl(-) binding sites within the selectivity filter stabilize ions by interactions with alpha-helix dipoles and by chemical interactions with nitrogen atoms and hydroxyl groups of residues in the protein. The Cl(-) binding site nearest the extracellular solution can be occupied either by a Cl(-) ion or by a glutamate carboxyl group. Mutations of this glutamate residue in Torpedo ray ClC channels alter gating in electrophysiological assays. These findings reveal a form of gating in which the glutamate carboxyl group closes the pore by mimicking a Cl(-) ion.     

The effect of a variable dielectric coefficient and finite ion size on Poisson-Boltzmann calculations of DNA-electrolyte systems.

The results of variable dielectric coefficient Poisson-Boltzmann calculations of the counter-ion concentration in the vicinity of an all-atom model of the B-form of DNA are presented with an emphasis on the importance of spatial variations in the dielectric properties of the solvent, particularly at the macro-ion-solvent interface. Calculations of the distribution of hard-sphere electrolyte ions of various dimensions are reported. The presence of a dielectric boundary significantly increases the magnitude of the electrostatic potential with a concomitant increase in the accumulation of small counter-ions in the groove regions of DNA. Because ions with radii greater than 2 A have restricted access to the minor groove, the effect there is less significant than it is within the major groove. Changes in the dielectric coefficient for the electrolyte solution, allowing variation from 10 to 25, 40, 60, and 78.5 within the first 7.4 A of the surface of DNA, substantially increases the calculated surface concentration of counter-ions of all sizes. A lower dielectric coefficient near the macro-ion surface also tends to increase the counter-ion density in regions where the electrostatic potential is more negative than -kT. Regardless of the choice of dielectric coefficient, the number of ions in regions where the electrostatic potential is less than -kT remains the same for 0.153 M added 1-1 monovalent electrolyte as for the case without added salt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monte Carlo determination of the distribution of ions about a cylindrical polyelectrolyte

We report a calculation of the distribution of small ions around a charged cylinder representing a polyelectrolyte molecule in solution. The Monte Carlo method of Metropolis, Rosenbluth, and Teller was used to avoid the inaccuracies known to be associated with the Poisson-Boltzmann equation. The systems examined contained a long polyelectrolyte cylinder with charge parameter, χ, equal to 4.2, corresponding approximately to a DNA molecule. In one model, the cylinder had charges on its axis and an exclusion radius to the center of the small ions equal to 10 Å, while the small ions had various radii in the range from 1 to 10 Å and one or two protonic charges. Various systems were studied; some had one species of small ion alone, others had mixtures of different types. The results showed good agreement with the solution of the Poisson-Boltzmann equation when only the species with 1-Å radius was present, but considerable discrepancies appeared with larger ions as a result of excluded volume interactions between the latter. Deviations from the Poisson-Boltzmann equation also appeared when both positive and negative small ions were present; the deviations were in the direction of a higher concentration of both counter- and co-ions, but particularly co-ions, close to the polyelectrolyte. In another model, the charges were arranged along two helices on the surface of the cylinder; the resulting radial distribution of small ions was not much different from that found when the charges were situated on the axis. In all cases there was a striking accumulation of counterions in a layer of concentration exceeding 1 mol/L at the surface of the polyion.     

A precise analytical method for calculating the electrostatic energy of macromolecules in aqueous solution

A new method for calculating the total electrostatic free energy of a macromolecule in solution is presented. It is applicable to molecules of arbitrary shape and size, including membranes or macromolecular assemblies with substrate molecules and ions. The method is derived from integrating the energy density of the electrostatic field and is termed the field energy method. It is based on the dielectric model, in which the solute and the surrounding water are regarded as different continuous dielectrics. The field energy method yields both the interaction energy between all charge pairs and the self energy of single charges, effectively accounting for the interaction with water. First, the dielectric boundary and mirror charges are determined for all charges of the solute. The energy is then given as a simple function of the interatomic distances, and the standard atomic partial charges and volumes. The interaction and self energy are shown to result from three-body and pairwise interactions. Both energy terms explicitly involve apolar atoms, revealing that apolar groups are also subject to electrostatic forces. We applied the field energy method to a spherical model protein. Comparison with the Kirkwood solution shows that errors are within a small percentage. As a further test, the field energy method was used to calculate the electrostatic potential of the protein superoxide dismutase. We obtained good agreement with the result from a program that implements the numerical finite difference algorithm. The field energy method provides a basis for energy minimization and dynamics programs that account for the solvent and screening effect of water at little computational expense.     

Anomalous mole fraction effect, electrostatics, and binding in ionic channels.

Ionic channels bathed in mixed solutions of two permeant electrolytes often conduct less current than channels bathed in pure solutions of either. For many years, this anomalous mole fraction effect (AMFE) has been thought to occur only in single-file pores containing two or more ions at a time. Most thinking about channels incorporates this view. We show here that the AMFE arises naturally, as an electrostatic consequence of localized ion specific binding, if the average current through a channel is described by a theory (Poisson-Nernst-Planck, PNP) that computes the average electric field from the average concentration of charges in and near the channel. The theory contains only those ion-ion interactions mediated by the mean field, and it does not enforce single filing. The AMFE is predicted by PNP over a wide range of mean concentrations of ions in the channel; for example, it is predicted when (on the average) less, or much less, than one ion is found in the channel's pore. In this treatment, the AMFE arises, in large measure, from a depletion layer produced near a region of ion-specific binding. The small excess concentration of ions in the binding region repels all nearby ions of like charge, thereby creating a depletion layer. The overall conductance of the channel arises in effect from resistors in series, one from the binding region, one from the depletion zone, and one from the unbinding region. The highest value resistor (which occurs in the depletion zone) limits the overall series conductance. Here the AMFE is not the result of single filing or multiple occupancy, and so previous views of permeation need to be revised: the presence of an AMFE does not imply that ions permeate single file through a multiply occupied pore.     

Further studies on the contribution of electrostatic and hydrophobic interactions to protein adsorption on dye-ligand adsorbents.

The adsorption equilibria of bovine serum albumin (BSA), gamma-globulin, and lysozyme to three kinds of Cibacron blue 3GA (CB)-modified agarose gels, 6% agarose gel-coated steel heads (6AS), Sepharose CL-6B, and a home-made 4% agarose gel (4AB), were studied. We show that ionic strength has irregular effects on BSA adsorption to the CB-modified affinity gels by affecting the interactions between the negatively charged protein and CB as well as CB and the support matrix. At low salt concentrations, the increase in ionic strength decreases the electrostatic repulsion between negatively charged BSA and the negatively charged gel surfaces, thus resulting in the increase of BSA adsorption. This tendency depends on the pore size of the solid matrix, CB coupling density, and the net negative charges of proteins (or aqueous - phase pH value). Sepharose gel has larger average pore size, so the electrostatic repulsion-effected protein exclusion from the small gel pores is observed only for the affinity adsorbent with high CB coupling density (15.4 micromol/mL) at very low ionic strength (NaCl concentration below 0.05 M in 10 mM Tris-HCl buffer, pH 7.5). However, because CB-6AS and CB-4AB have a smaller pore size, the electrostatic exclusion effect can be found at NaCl concentrations of up to 0.2 M. The electrostatic exclusion effect is even found for CB-6AS with a CB density as low as 2.38 micromol/mL. Moreover, the electrostatic exclusion effect decreases with decreasing aqueous-phase pH due to the decrease of the net negative charges of the protein. For gamma-globulin and lysozyme with higher isoelectric points than BSA, the electrostatic exclusion effect is not observed. At higher ionic strength, protein adsorption to the CB-modified adsorbents decreases with increasing ionic strength. It is concluded that the hydrophobic interaction between CB molecules and the support matrix increases with increasing ionic strength, leading to the decrease of ligand density accessible to proteins, and then the decrease of protein adsorption. Thus, due to the hybrid effect of electrostatic and hydrophobic interactions, in most cases studied there exists a salt concentration to maximize BSA adsorption.     

Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions

Multi-ion pore behaviour has been identified in many Cl(-) channel types but its biophysical significance is uncertain. Here, we show that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel that disrupt anion-anion interactions within the pore are associated with drastically reduced single channel conductance. These results are consistent with models suggesting that rapid Cl(-) permeation in CFTR results from repulsive ion-ion interactions between Cl(-) ions bound concurrently inside the pore. Naturally occurring mutations that disrupt these interactions can result in cystic fibrosis.     

DNA like-charge attraction and overcharging by divalent counterions in the presence of divalent co-ions

Strongly correlated electrostatics of DNA systems has drawn the interest of many groups, especially the condensation and overcharging of DNA by multivalent counterions. By adding counterions of different valencies and shapes, one can enhance or reduce DNA overcharging. In this paper, we focus on the effect of multivalent co-ions, specifically divalent co-ions such as SO\(_{4}^{2-}\). A computational experiment of DNA condensation using Monte Carlo simulation in grand canonical ensemble is carried out where the DNA system is in equilibrium with a bulk solution containing a mixture of salt of different valency of co-ions. Compared to systems with purely monovalent co-ions, the influence of divalent co-ions shows up in multiple aspects. Divalent co-ions lead to an increase of monovalent salt in the DNA condensate. Because monovalent salts mostly participate in linear screening of electrostatic interactions in the system, more monovalent salt molecules enter the condensate leads to screening out of short-range DNA–DNA like charge attraction and weaker DNA condensation free energy. The overcharging of DNA by multivalent counterions is also reduced in the presence of divalent co-ions. Strong repulsions between DNA and divalent co-ions and among divalent co-ions themselves lead to a depletion of negative ions near the DNA surface as compared to the case without divalent co-ions. At large distances, the DNA–DNA repulsive interaction is stronger in the presence of divalent co-ions, suggesting that divalent co-ions’ role is not only that of simple stronger linear screening.     

GCEMC Simulations of “Swiss Cheese” Ion Exchange Membranes in Dilute Solutions of Primitive Model 1:1 Electrolytes with Different Sizes of Ions or 2:1 Electrolytes with Different Bjerrum Parameters

Abstract

Monte Carlo simulations using a Markov process corresponding to a (generalized) Grand Canonical Ensemble have been performed for a number of spherical micropores in equilibrium with dilute external bulk solutions of primitive model electrolytes. Dilute solutions of 1:1 electrolytes with a Bjerrum parameter B = 1.546 with cations three times larger than the anions have been simulated. Also, dilute solutions of 2:1 electrolytes with ions of equal size and reduced Bjerrum parameters B_r = 1.546 and 3 have been simulated. The pores are primitive pores with hard walls and the same dielectric permittivity in the wall and in the pore solution. They range from a pore radius = 5 times the mean ionic diameter to 35 times this diameter, and they carry a fixed charge equal to + 5,0 and ?5 elementary charges. The fixed charge is modelled as smoothly distributed on the pore-wall interface. In addition to the electric potential of the interfacial charge and the electric potential of the spherical double layer, a potential Δ between the pore solution and the bulk solution may be deliberately added. For single pores we may take Δ = 0, but then the pore is generally not electroneutral. In a “Swiss cheese” membrane with a lot of (equally sized) pores, the membrane phase has to approach electroneutrality for growing size of the phase. This is approximated by means of a membrane generated potential Δ in each pore (from the electrostatic interactions with the other pores). The potential A so chosen to obtain electroneutrality is the GCEMC Donnan potential. These non-ideal Donnan potentials are compared to the ideal values (with activity coefficients equal to zero). From the mean occupation numbers of cations and anions in the pores, the average pore values of the mean ionic and the single ionic activity coefficients of the ions are calculated. These are very dependent on pore sizes and on the potential in the pore. The excess energy and the electrostatic Helmholtz free energy of the ions in the pores are also simulated directly. The electrostatic entropy is found as the difference.