Itamar Borukhov

STERIC EFFECTS IN ELECTROLYTES : A MODIFIED POISSON-BOLTZMANN EQUATION

The adsorption of large ions from solution to a charged surface is investigated theoretically. A generalized Poisson-Boltzmann equation which takes into account the finite size of the ions is presented. We obtain analytical expressions for the electrostatic potential and ion concentrations at the surface, leading to a modified Grahame equation. At high surface charge densities the ionic concentration saturates to its maximum value. Our results are in agreement with recent experiments.

Adsorption of large ions from an electrolyte solution: a modified Poisson–Boltzmann equation

Abstract The behavior of electrolyte solutions close to a charged surface is studied theoretically. A modified Poisson–Boltzmann equation that takes into account the volume excluded by the ions in addition to the electrostatic interactions is presented. In a formal lattice gas formalism the modified Poisson–Boltzmann equation can be obtained from a mean-field approximation of the partition function. In an alternative phenomenological approach, the same equation can be derived by including the entropy of the solvent molecules in the free energy. In order to visualize the effect of steric repulsion, a simple case of a single, highly charged, flat surface is discussed. This situation resembles recent adsorption experiments of large ions onto a charged monolayer. A simple criterion for the importance of the steric effects is expressed in terms of the surface charge density and the size of the ions. It is shown that when these effects are important a saturated layer is formed near the surface. A modified Grahame equation relating the ion concentration at the surface to the surface charge density is obtained.

Structural polymorphism of the cytoskeleton: A model of linker-assisted filament aggregation

The phase behavior of charged rods in the presence of interrod linkers is studied theoretically as a model for the equilibrium behavior underlying the organization of actin filaments by linker proteins in the cytoskeleton. The presence of linkers in the solution modifies the effective interrod interaction and can lead to interfilament attraction. Depending on the composition and physical properties of the system, such as linker-binding energies, filaments will orient either perpendicular or parallel to each other, leading to network-like or bundled structures. We show that such a system can have one of three generic phase diagrams, one dominated by bundles, another by networks, and the third containing both bundle and network-like phases. The first two diagrams can be found over a wide range of interaction energies, whereas the third diagram occurs only for a narrow range. These results provide theoretical understanding of the classification of linker proteins as bundling proteins or crosslinking proteins. In addition, they suggest possible mechanisms by which the cell may control cytoskeletal morphology.

Effect of mono- and multivalent salts on angle-dependent attractions between charged rods.

Using molecular dynamics simulations we examine the effective interactions between two like-charged rods as a function of angle and separation. In particular, we determine how the competing electrostatic repulsions and multivalent-ion-induced attractions depend upon concentrations of simple and multivalent salts. We find that with increasing multivalent salt, the stable configuration of two rods evolves from isolated rods to aggregated perpendicular rods to aggregated parallel rods; at sufficiently high concentration, additional multivalent salt reduces the attraction. Monovalent salt enhances the attraction near the onset of aggregation and reduces it at a higher concentration of multivalent salt.

Identification of Widespread Ultra-Edited Human RNAs

Adenosine-to-inosine modification of RNA molecules (A-to-I RNA editing) is an important mechanism that increases transciptome diversity. It occurs when a genomically encoded adenosine (A) is converted to an inosine (I) by ADAR proteins. Sequencing reactions read inosine as guanosine (G); therefore, current methods to detect A-to-I editing sites align RNA sequences to their corresponding DNA regions and identify A-to-G mismatches. However, such methods perform poorly on RNAs that underwent extensive editing (“ultra”-editing), as the large number of mismatches obscures the genomic origin of these RNAs. Therefore, only a few anecdotal ultra-edited RNAs have been discovered so far. Here we introduce and apply a novel computational method to identify ultra-edited RNAs. We detected 760 ESTs containing 15,646 editing sites (more than 20 sites per EST, on average), of which 13,668 are novel. Ultra-edited RNAs exhibit the known sequence motif of ADARs and tend to localize in sense strand Alu elements. Compared to sites of mild editing, ultra-editing occurs primarily in Alu-rich regions, where potential base pairing with neighboring, inverted Alus creates particularly long double-stranded RNA structures. Ultra-editing sites are underrepresented in old Alu subfamilies, tend to be non-conserved, and avoid exons, suggesting that ultra-editing is usually deleterious. A possible biological function of ultra-editing could be mediated by non-canonical splicing and cleavage of the RNA near the editing sites.

Polyelectrolyte Solutions between Charged Surfaces

The effect of electrostatic interactions on the distribution of polymers in a good solvent is investigated for semi-dilute solutions containing charged polymers (polyelectrolytes) and small ions. A mean field approach is used to derive two coupled differential equations: a modified Poisson-Boltzmann equation for the electrostatic potential, and a self-consistent field equation for the polymer order parameter. We compare several monomer charge distributions; smeared, annealed and quenched. The polymers are confined between two charged surfaces, and are in contact with a reservoir of polymers and electrolyte. This makes the annealed and quenched cases equivalent. Non-monotonous profiles are obtained for the case of competing surface interactions: electrostatic adsorption vs. short-range desorption.

Stabilizing grafted colloids in a polymer melt: Favorable enthalpic interactions

The interactions between spherical colloids covered with end-grafted polymers (brushes) immersed in a polymer melt are studied theoretically. We show that attractive enthalpic interactions between the two polymer species, characterized by a negative Flory parameter (chi<0), can stabilize the colloidal dispersion. The stabilizing mechanism is a result of a structural change from a dry brush, where the melt chains do not penetrate deeply into the brush, to a wet brush, where the free chains penetrate the brush and force the grafted chains to extend into the melt.

Association of two semiflexible polyelectrolytes by interchain linkers: Theory and simulations

The aggregation of two highly charged semiflexible polyelectrolytes in the presence of generalized linkers is studied theoretically. This model provides insight into biological processes such as DNA condensation and F-actin self-assembly induced by either multivalent counterions or bundling proteins. The interplay between the bending rigidity of the chains and their electrostatic interactions leads to an effective interlinker interaction that is repulsive at large distances and attractive at short ones. We find a rounded phase transition from a dilute linker gas where the chains form large loops to a dense disordered linker fluid where the chains are almost parallel. The onset of chain pairing occurs as soon as the free energy of a pair of chains becomes lower than that of two isolated chains and is located well within the crossover regime between the two linker phases. Our main findings are confirmed by molecular dynamics simulations of two semiflexible charged chains in a mixture of monovalent and polyv...

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

Blocking conformational changes in biologically active proteins holds therapeutic promise. Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helix–helix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices. Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations. In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNFα, IL-1β, IL-6, and IL-8 induced by endotoxin by >80%. When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNFα, IL-6, and IFNγ by >50%. The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer. Also, the predicted mode of action of the active peptides was experimentally verified. Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices. These data demonstrate a previously uncharacterized method for rational design of protein antagonists.

Adsorption of polyelectrolytes and inter-colloidal forces

The effect of charged polymers on the interactions between charged surfaces in solution is investigated theoretically. We use mean-field theory to derive a self-consistent field equation for the polymer order parameter, and a modified Poisson–Boltzmann equation for the electrostatic potential. The two differential equations together with the appropriate boundary conditions are solved numerically. We use simple scaling arguments to investigate the adsorption characteristics to a single surface in the strong electrostatic regime. We obtain simple expressions for the dependence of the adsorbed amount Γ on the charge fraction p and the salt concentration cb, in good agreement with experiments. The forces between two charged surfaces in the presence of polyelectrolytes are calculated using a generalized contact theorem. We obtain repulsion as well as attraction between equally charged surfaces.