The interfacial electrostatic potential modulates the insertion of cell-penetrating peptides into lipid bilayers.

Cell-penetrating peptides (CPP) are short sequences of cationic amino-acids that show a surprising ability to traverse lipid bilayers. CPP are considered to be some of the most effective vectors to introduce membrane-impermeable cargos into cells, but the molecular basis of the membrane translocation mechanisms and its dependence on relevant membrane physicochemical properties have yet to be fully determined. In this paper we resort to Molecular Dynamics simulations and experiments to investigate how the electrostatic potential across the lipid/water interface affects the insertion of hydrophilic and amphipathic CPP into two-dimensional lipid structures. Simulations are used to quantify the effect of the transmembrane potential on the free-energy profile associated with the transfer of the CPP across a neutral lipid bilayer. It is found that the electrostatic bias has a relatively small effect on the binding of the peptides to the membrane surface, but that it significantly lowers the permeation barrier. A charge compensation mechanism, arising from the segregation of counter-ions while the peptide traverses the membrane, determines the shape and symmetry of the free-energy curves and underlines relevant mechanistic considerations. Langmuir monolayer experiments performed with a variety of amphiphiles model the incorporation of the CPP into the external membrane leaflet. It is shown that the dipole potential of the monolayer controls the extent of penetration of the CPP into the lipid aggregate, to a greater degree than its surface charge.

Nano-indentation of a room-temperature ionic liquid film on silica: a computational experiment.

We investigate the structure of the [bmim][Tf(2)N]/silica interface by simulating the indentation of a thin (4 nm) [bmim][Tf(2)N] film by a hard nanometric tip. The ionic liquid/silica interface is represented in atomistic detail, while the tip is modelled by a spherical mesoscopic particle interacting via an effective short-range potential. Plots of the normal force (F(z)) on the tip as a function of its distance from the silica surface highlight the effect of weak layering in the ionic liquid structure, as well as the progressive loss of fluidity in approaching the silica surface. The simulation results for F(z) are in near-quantitative agreement with new AFM data measured on the same [bmim][Tf(2)N]/silica interface under comparable thermodynamic conditions.

Melting of a tetrahedral network model of silica.

Thermal properties of an idealised tetrahedral network model of silica are investigated by Monte Carlo simulations. The interatomic potential consists of anharmonic stretching and bending terms, plus a short range repulsion. The model includes a bond interchange rule similar to the well known Wooten, Winer and Weaire (WWW) algorithm (see Phys. Rev. Lett., 1985, 54, 1392). Simulations reveal an apparent first order melting transition at T = 2200 K. The computed changes in the local coordination upon melting are consistent with experimental and ab initio data.

Mesophases in nearly 2D room-temperature ionic liquids.

Computer simulations of (i) a [C(12)mim][Tf(2)N] film of nanometric thickness squeezed at kbar pressure by a piecewise parabolic confining potential reveal a mesoscopic in-plane density and composition modulation reminiscent of mesophases seen in 3D samples of the same room-temperature ionic liquid (RTIL). Near 2D confinement, enforced by a high normal load, as well as relatively long aliphatic chains are strictly required for the mesophase formation, as confirmed by computations for two related systems made of (ii) the same [C(12)mim][Tf(2)N] adsorbed at a neutral solid surface and (iii) a shorter-chain RTIL ([C(4)mim][Tf(2)N]) trapped in the potential well of part i. No in-plane modulation is seen for ii and iii. In case ii, the optimal arrangement of charge and neutral tails is achieved by layering parallel to the surface, while, in case iii, weaker dispersion and packing interactions are unable to bring aliphatic tails together into mesoscopic islands, against overwhelming entropy and Coulomb forces. The onset of in-plane mesophases could greatly affect the properties of long-chain RTILs used as lubricants.

Interaction of room temperature ionic liquid solutions with a cholesterol bilayer.

Water solutions of representative ([C4mim][Cl] and [C4mim][Tf2N]) room temperature ionic liquids (ILs) in contact with a neutral lipid bilayer made of cholesterol molecules has been investigated by molecular dynamics simulations based on an empirical force field model. The results show that both ILs display selective adsorption at the water-cholesterol interface, with partial inclusion of ions into the bilayer. In the case of [C4mim][Cl], the adsorption of ions at the water-cholesterol interface is limited by a sizable bulk solubility of the IL, driven by the high water affinity of [Cl]-. The relatively low solubility of [C4mim][Tf2N], instead, gives rise to a nearly complete segregation of the IL component on the bilayer, altering its volume, compressibility, and electrostatic environment. The computational results display important similarities to the results of recent experimental measurements for ILs in contact with phospholipid model membranes (see Evans, K. O. Int. J. Mol. Sci. 2008, 9, 498-511 and references therein).

Amphiphilic character and aggregation properties of small cholesterol islands on water: a simulation study.

Small cholesterol clusters (Ch(n), 1 < or = n < or = 10) on water have been investigated by molecular dynamics simulations based on an empirical force field potential. The simulation results for clusters of increasing size highlight the processes that take place during the initial stages of cholesterol aggregation at low coverage. Our results show that at T = 280 K clusters form spontaneously out of a dilute two-dimensional (2D) vapor of cholesterol molecules, driven by entropy and potential energy. Up to n = 10, corresponding to 25% coverage for our simulation cell, cholesterol molecules lay flat on the water surface, forming fluid-like 2D aggregates. Within each island, the elongated cholesterol molecules align their longest axis along a common direction, anticipating the liquid-crystal character of bulk phases. With increasing cluster size, the adsorption energy per molecule quickly saturates to a value close to the limiting value for a full monolayer coverage. Cholesterol adsorption locally changes the electrostatic surface polarization of water, giving rise to an induced moment that tends to compensate the dipole of the adsorbed island. Computations for a single cholesterol molecule and dimer in bulk water are reported for a comparison. The absorption energy of both species in bulk water is larger than their adsorption energy at the water surface, thus pointing to entropy as the origin of the amphiphilic character of cholesterol.

Nanometric ionic-liquid films on silica: a joint experimental and computational study.

Atomic force microscopy images for [bmim][Tf(2)N] films deposited at ambient conditions by drop-casting show a population of terraced islands of mesoscopic area (1-100 µ(2)) and ∼50 nm height. The regularity of terraces and steps, stiff mechanical properties and a fragile fracture mode all suggest that the islands are solid-like, even though bulk [bmim][Tf(2)N] is liquid at the temperature of the experiment. Molecular dynamics simulations for a homogeneous [bmim][Tf(2)N] film 4 nm thick on silica also display marked layering in proximity to silica of periodicity closely matching the experimental estimate of the step height. The density modulation of the simulated sample, however, decays into an approximatively homogeneous and fluid-like density distribution ∼2 nm from the solid surface. The detailed comparison of experiments and simulations is contained in the closing section of the paper.

Ion association in [bmim][PF6]/naphthalene mixtures: an experimental and computational study.

Mixtures of room temperature ionic liquids (IL) with neutral organic molecules provide a valuable testing ground to investigate the interplay of the ionic and molecular-dipolar state in dense Coulomb systems at near ambient conditions. In the present study, the viscosity eta and the ionic conductivity sigma of 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6])/naphthalene mixtures at T = 80 degrees C have been measured at 10 stoichiometries spanning the composition range from pure naphthalene to pure [bmim][PF6]. The viscosity grows nearly monotonically with increasing IL mole fraction ( x), whereas the conductivity per ion displays a clear peak at x approximately 15%. The origin of this maximum has been investigated using molecular dynamics simulations based on a classical force field. Snapshots of the simulated samples show that the conductivity maximum is due to the gradual transition in the IL component from an ionic state at high x to a dipolar fluid made of neutral ion pairs at low x. At concentrations x < 0.20 the ion pairs condense into molecular-thin filaments bound by dipolar forces and extending in between nanometric droplets of IL. These results are confirmed and complemented by the computation of dynamic and transport properties in [bmim][PF6]/naphthalene mixtures at low IL concentration.

Melting behavior of an idealized membrane model.

The melting behavior of an idealized model giving rise to two-dimensional (2D) structures at low temperature and low density is investigated by Monte Carlo simulations. The system is made of particles carrying a spin of constant length and variable orientation, whose potential energy is the sum of a repulsive spherical pair interaction, and of a spin-spin contribution, reminiscent of but essentially different from the electrostatic dipole-dipole interaction. The simulation results show that the model phase diagram is determined by the interplay of a ferro- to paraelectric transition in the spin part and of the solid to fluid transition found in simple pair-potential models. The 2D solid melts into a three-dimensional (3D) fluid when the spin-spin interaction is weak. Strong spin-spin interactions give rise to two transitions, the first one corresponding to the melting of the 2D solid into a 2D fluid, and the second one corresponding to the crossover from a 2D to a 3D fluid. The fluid phase stable in between these two transitions provides a model for the liquid state arising in organic and biological membranes across their main transition.

Local and semilocal density functional computations for crystals of 1-alkyl-3-methyl-imidazolium salts.

The accuracy and reliability of popular density functional approximations for the compounds giving origin to room temperature ionic liquids have been assessed by computing the T=0 K crystal structure of several 1-alkyl-3-methyl-imidazolium salts. Two prototypical exchange-correlation approximations have been considered, i.e., the local density approximation (LDA) and one gradient corrected scheme [PBE-GGA, Phys. Rev. Lett. 77, 3865 (1996)]. Comparison with low-temperature x-ray diffraction data shows that the equilibrium volume predicted by either approximations is affected by large errors, nearly equal in magnitude (approximately 10%), and of opposite sign. In both cases the error can be traced to a poor description of the intermolecular interactions, while the intramolecular structure is fairly well reproduced by LDA and PBE-GGA. The PBE-GGA optimization of atomic positions within the experimental unit cell provides results in good agreement with the x-ray structure. The correct system volume can also be restored by supplementing PBE-GGA with empirical dispersion terms reproducing the r-6 attractive tail of the van der Waals interactions.

Neutral and charged 1-butyl-3-methylimidazolium triflate clusters: equilibrium concentration in the vapor phase and thermal properties of nanometric droplets.

Ground state energy, structure, and harmonic vibrational modes of 1-butyl-3-methylimidazolium triflate ([bmim][Tf]) clusters have been computed using an all-atom empirical potential model. Neutral and charged species have been considered up to a size (30 [bmim][Tf] pairs) well into the nanometric range. Free energy computations and thermodynamic modeling have been used to predict the equilibrium composition of the vapor phase as a function of temperature and density. The results point to a nonnegligible concentration of very small charged species at pressures (P approximately 0.01 Pa) and temperatures (T >or= 600 K) at the boundary of the stability range of [bmim][Tf]. Thermal properties of nanometric neutral droplets have been investigated in the 0

Polarization relaxation in an ionic liquid confined between electrified walls.

The response of a room temperature molten salt to an external electric field when it is confined to a nanoslit is studied by molecular dynamics simulations. The fluid is confined between two parallel and oppositely charged walls, emulating two electrified solid-liquid interfaces. Attention is focused on structural, electrostatic, and dynamical properties, which are compared with those of the nonpolarized fluid. It is found that the relaxation of the electrostatic potential, after switching the electric field off, occurs in two stages. A first, subpicosecond process accounts for 80% of the decay and is followed by a second subdiffusive process with a time constant of 8 ps. Diffusion is not involved in the relaxation, which is mostly driven by small anion translations. The relaxation of the polarization in the confined system is discussed in terms of the spectrum of charge density fluctuations in the bulk.

Simple models of complex aggregation: vesicle formation by soft repulsive spheres with dipolelike interactions.

Structural and thermodynamic properties of spherical particles carrying classical spins are investigated by Monte Carlo simulations. The potential energy is the sum of short range, purely repulsive pair contributions, and spin-spin interactions. These last are of the dipole-dipole form, with however, a crucial change of sign. At low density and high temperature the system is a homogeneous fluid of weakly interacting particles and short range spin correlations. With decreasing temperature particles condense into an equilibrium population of free floating vesicles. The comparison with the electrostatic case, giving rise to predominantly one-dimensional aggregates under similar conditions, is discussed. In both cases condensation is a continuous transformation, provided the isotropic part of the interatomic potential is purely repulsive. At low temperature the model allows us to investigate thermal and mechanical properties of membranes. At intermediate temperatures it provides a simple model to investigate equilibrium polymerization in a system giving rise to predominantly two-dimensional aggregates.

Simulation of the surface structure of butylmethylimidazolium ionic liquids.

Molecular dynamics simulations of the liquid/vacuum surfaces of the room temperature ionic liquids [bmim][PF(6)], [bmim][BF(4)] and [bmim][Cl] have been carried out at various temperatures. The surfaces are structured with a top monolayer containing oriented cations and anions. The butyl side chains tend to face the vacuum and the methyl side chains the liquid. However, as the butyl chains are not densely packed, both anions and rings are visible from the vacuum phase. The effects of temperature and the anion on the degree of cation orientation is small, but the potential drop from the vacuum to the interior of the liquid is greater for liquids with smaller anions. We compare the simulation results with a range of experimental observations and suggest that neutron reflection from samples with protiated butyl groups would be a sensitive probe of the structure.

Simulation of interfaces between room temperature ionic liquids and other liquids.

The structure and properties of the interfaces between the room temperature ionic liquid dimethylimidazolium chloride ([dmim]Cl) and different Lennard-Jones fluids and between ionic liquid and water have been studied by molecular dynamics simulations, and compared to the ionic liquid-vapour interface. Two contrasting types of interface were investigated, thermodynamically stable interfaces between ionic liquid and vapour and between ionic liquid and Lennard-Jones fluids, and diffusing interfaces between miscible phases of different compositions involving water. The density profiles of different species through the interface are presented. The cations and water molecules near the former type of interface are aligned relative to the surface, but no orientational preference was found near or in the broad diffusing interface. The ionic liquid has a negative electrostatic potential relative to vapour or Lennard-Jones fluid, but is more positive than pure water. This contrast is explained in terms of the relative importance of orientation and concentration differences in the two types of interface.