Multiscale Modeling of Aqueous Electric Double Layers.

From the stability of colloidal suspensions to the charging of electrodes, electric double layers play a pivotal role in aqueous systems. The interactions between interfaces, water molecules, ions and other solutes making up the electrical double layer span length scales from Ångströms to micrometers and are notoriously complex. Therefore, explaining experimental observations in terms of the double layer's molecular structure has been a long-standing challenge in physical chemistry, yet recent advances in simulations techniques and computational power have led to tremendous progress. In particular, the past decades have seen the development of a multiscale theoretical framework based on the combination of quantum density functional theory, force-field based simulations and continuum theory. In this Review, we discuss these theoretical developments and make quantitative comparisons to experimental results from, among other techniques, sum-frequency generation, atomic-force microscopy, and electrokinetics. Starting from the vapor/water interface, we treat a range of qualitatively different types of surfaces, varying from soft to solid, from hydrophilic to hydrophobic, and from charged to uncharged.

Interplay of Interfacial Viscosity, Specific-Ion, and Impurity Adsorption Determines Zeta Potentials of Phospholipid Membranes.

Ion-specific induced changes of the ζ-potential of phospholipid vesicles are commonly used to quantify the affinity of different ions to the lipid interface. The negative ζ-potential of zwitterionic net-neutral phospholipid vesicles in neat water, which changes sign and increases in solutions of NaCl or KCl, is a phenomenon consistently observed in experiments but not fully understood theoretically. Using atomistic molecular dynamics simulations in the presence of applied electric fields which drive electroosmotic flows, in combination with an electrostatic continuum model based on the modified Poisson-Boltzmann and Helmholtz-Smoluchowski equations, we study the electrokinetic and electrostatic properties as well as the specific ion affinities to the phospholipid-water interface, in order to resolve these puzzling observations. Our modified continuum equations account for the dielectric profile at the lipid-water interface, ion-specific interactions between ions and the lipid-water interface, and the interfacial viscosity profile, which are all extracted from our atomistic simulations and rather accurately predict ion-density and electrostatic-potential distributions as well as ζ-potentials in comparison with our atomistic simulations. Our continuum model can explain experimental ζ-potentials only when we assume minute amounts of surface-active anionic impurities in the aqueous solution. In fact, the amount of impurities needed to explain the experimental data increases linearly with the salt concentration, suggesting that surface-active species, which might be already present in the lab water or lipid samples, could further be introduced through the added salt.

Particle Diffusivity and Free-Energy Profiles in Hydrogels from Time-Resolved Penetration Data.

A combined experimental and theoretical method to simultaneously determine diffusivity and free-energy profiles of particles that penetrate into inhomogeneous hydrogel systems is presented. As the only input, arbitrarily normalized concentration profiles from fluorescence intensity data of labeled tracer particles for different penetration times are needed. The method is applied to dextran molecules of varying size that penetrate into hydrogels of polyethylene-glycol chains with different lengths that are covalently cross-linked by hyperbranched polyglycerol hubs. Extracted dextran bulk diffusivities agree well with fluorescence correlation spectroscopy data obtained separately. Empirical scaling laws for dextran diffusivities and free energies inside the hydrogel are identified as a function of the dextran mass. An elastic free-volume model that includes dextran as well as polyethylene-glycol linker flexibility quantitively describes the repulsive dextran-hydrogel interaction free energy, which is of steric origin, and furthermore suggests that the hydrogel mesh-size distribution is rather broad and particle penetration is dominated by large hydrogel pores. Particle penetration into hydrogels for steric particle-hydrogel interactions is thus suggested to be governed by an elastic size-filtering mechanism that involves the tail of the hydrogel pore-size distribution.

Universal and Nonuniversal Aspects of Electrostatics in Aqueous Nanoconfinement.

Dielectric water properties, which significantly change in confinement, determine electrostatic interactions and thereby influence all molecular forces and chemical reactions. We present comparative simulations of water between graphene sheets, decanol monolayers, and phospholipid and glycolipid bilayers. Generally, dielectric profiles strongly differ in perpendicular and parallel surface directions and for large surface separation decay to the bulk value 1-2 nm away from the surface. Polar surface groups enhance the local interfacial dielectric response and for phospholipid bilayers induce a giant parallel contribution. A mapping on a box model with asymptotically determined effective water layer widths demonstrates that the perpendicular effective dielectric constant for all systems decreases for confinement below a nanometer, while the parallel one stays rather constant. The confinement-dependent perpendicular effective dielectric constant for graphene is in agreement with experimental data only if the effective water layer width is suitably adjusted. The interactions between two charges at small separation depend on the product of parallel and perpendicular effective water dielectric components; for large separation the interactions depend on the confining medium. For metallic confining media the interactions at large separation decay exponentially with a decay length that depends on the ratio of the effective parallel and perpendicular water dielectric components.

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy.

Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream formulation, dexamethasone (Dx), a synthetic glucocorticoid frequently used for the treatment of inflammatory skin diseases, was covalently linked with the paramagnetic probe 3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) to DxPCA. To investigate the penetration efficiency between these two vehicles, electron paramagnetic resonance (EPR) spectroscopy was used, which allows the quantification of a spin-labeled drug in different skin layers and the monitoring of the drug release. The penetration behavior in excised healthy and barrier-disrupted porcine skin was monitored by EPR, and subsequently analyzed using a numerical diffusion model. As a result, diffusion constants and free energy values in the different layers of the skin were identified for both formulations. Dx-nanocrystals showed a significantly increased drug amount that penetrated into viable epidermis and dermis of intact (factor 3) and barrier-disrupted skin (factor 2.1) compared to the base cream formulation. Furthermore, the observed fast delivery of the spin-labeled drug into the skin (80% DxPCA within 30 min) and a successive release from the aggregate unit into the viable tissue makes these nanocrystals very attractive for clinical applications.

Unraveling the Origin of the Apparent Charge of Zwitterionic Lipid Layers.

The structure of water molecules in contact with zwitterionic lipid molecules is of great biological relevance, because biological membranes are largely composed of such lipids. The interaction of the interfacial water molecules with the amphiphilic lipid molecules drives the formation of membranes and greatly influences various processes at the membrane surface, as the field that arises from the aligned interfacial water molecules masks the charges of the lipid headgroups from the approaching metabolites. To increase our understanding of the influence of water molecules on biological processes we study their structure at the interface using sum-frequency generation spectroscopy and molecular dynamics simulations. Interestingly, we find that water molecules at zwitterionic lipid molecules are mainly oriented by the field arising between the two oppositely charged molecular moieties within the lipid headgroups.

Influence of polar co-solutes and salt on the hydration of lipid membranes.

The influence of the co-solutes TMAO, urea, and NaCl on the hydration repulsion between lipid membranes is investigated in a combined experimental/simulation approach. Pressure-hydration curves obtained via sorption experiments reveal that the repulsion significantly increases when the membranes are loaded with co-solutes, most strongly for TMAO. As a result, the co-solutes retain additional water molecules and therefore provide membranes with a fluid and more physiological environment. The experimental data are quantitatively reproduced in complementary solvent-explicit atomistic molecular dynamics simulations, which yield the chemical potential of water. Simulation analysis reveals that the additional repulsion arises from the osmotic pressure generated by the co-solutes, an effect which is maximal for TMAO, due to its unfavorable interactions with the lipid headgroup layer and its extraordinarily high osmotic coefficient.

Effects of Urea and TMAO on Lipid Self-Assembly under Osmotic Stress Conditions.

Most land-living organisms regularly experience dehydration. In nature, one commonly applied strategy to protect against this osmotic stress is to introduce small polar molecules with low vapor pressure, commonly called osmolytes. Two examples of naturally occurring small polar compounds are urea and trimethylamine N-oxide (TMAO), which are known to have counteracting effects on protein stability. In this work, we investigate the effects of urea and TMAO on lipid self-assembly at varying water contents, focusing on dehydrated conditions. By using complementary experimental techniques, including sorption microcalorimetry, NMR, and X-ray scattering, together with molecular dynamics simulations in model systems composed of phosphatidylcholine lipids, water, and solute, we characterize interactions and self-assembly over a large range of hydration conditions. It is shown that urea and TMAO show qualitatively similar effects on lipid self-assembly at high water contents, whereas they have clearly different effects in dehydrated conditions. The latter can be explained by differences in the molecular interactions between the solutes and the lipid headgroups. TMAO is repelled from the bilayer interface, and it is thereby expelled from lipid lamellar systems with low water contents and narrow inter-bilayer regions. In these conditions, TMAO shows no effect on the lipid phase behavior. Urea, on the other hand, shows a slight affinity for the lipid headgroup layer, and it is present in the lipid lamellar system at all water contents. As a result, urea may exchange with water in dry conditions and thereby prevent dehydration-induced phase transitions. In nature, urea and TMAO are sometimes found together in the same organisms and it is possible that their combined effect is to both protect lipid membranes against dehydration and still avoid denaturation of proteins.

Hair bundles of cochlear outer hair cells are shaped to minimize their fluid-dynamic resistance.

The mammalian sense of hearing relies on two types of sensory cells: inner hair cells transmit the auditory stimulus to the brain, while outer hair cells mechanically modulate the stimulus through active feedback. Stimulation of a hair cell is mediated by displacements of its mechanosensitive hair bundle which protrudes from the apical surface of the cell into a narrow fluid-filled space between reticular lamina and tectorial membrane. While hair bundles of inner hair cells are of linear shape, those of outer hair cells exhibit a distinctive V-shape. The biophysical rationale behind this morphology, however, remains unknown. Here we use analytical and computational methods to study the fluid flow across rows of differently shaped hair bundles. We find that rows of V-shaped hair bundles have a considerably reduced resistance to crossflow, and that the biologically observed shapes of hair bundles of outer hair cells are near-optimal in this regard. This observation accords with the function of outer hair cells and lends support to the recent hypothesis that inner hair cells are stimulated by a net flow, in addition to the well-established shear flow that arises from shearing between the reticular lamina and the tectorial membrane.