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We address the problem of the quantitative prediction of micelle formation in dilute aqueous solutions of ionic surfactants using sodium dodecyl sulfate (SDS) as a model system through a computational approach that involves three steps: (a) execution of coarse-grained simulations based on the MARTINI force field (with slightly modified parameters to afford the formation of large micelles); (b) reverse mapping of the final self-assembled coarse-grained configuration into an all-atom configuration; and (c) final relaxation of this all-atom configuration through short-time (on the order of a few tens of nanoseconds), detailed isothermal-isobaric molecular dynamics simulations using the CHARMM36 force field. For a given concentration of the solution in SDS molecules, the modified MARTINI-based coarse-grained simulations lead to the formation of large micelles characterized by mean aggregation numbers above the experimentally observed ones. However, by reintroducing the detailed chemical structure through a strategy that solves a well-defined geometric problem and re-equilibrating, these large micellar aggregates quickly dissolve to smaller ones and equilibrate to sizes that perfectly match the average micelle size measured experimentally at the given surfactant concentration. From the all-atom molecular dynamics simulations, we also deduce the surfactant diffusivity DSDS and the zero-shear rate viscosity, η0, of the solution, which are observed to compare very favorably with the few experimental values that we were able to find in the literature.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

The skin surface, our first barrier against the external environment, is covered by the sebum oil, a lipid film composed of sebaceous and epidermal lipids, which is important in the regulation of the hydration level of our skin. Here, we investigate the pathways leading to the transfer of epidermal lipids from the skin lipid bilayer to the sebum. We show that the sebum triglycerides, a major component of sebum, interact strongly with the epidermal lipids and extract them from the bilayer. Using microsecond time scale molecular dynamics simulations, we identify and quantify the free energy associated with the skin lipid extraction process.

In recent years, sebum oil has been found to play a key role in the regulation of the hydration of the outermost layer of the skin, the stratum corneum. Understanding how a major component of the sebum oil, the triglyceride tri-cis-6-hexadecenoin (TG), interacts with water is an important step in gaining insight into the water regulation function of the sebum oil. Here we use molecular dynamics simulations to investigate the structural and interfacial properties of TG in bulk and at the air and water interface. Our model performs very well in reproducing experimental results, such as density, surface tensions and surface pressure area isotherms. We show that triglyceride molecules in the liquid phase assemble together, through the glycerol group, forming a single percolating network. TG-air interfaces orient the lipids with the interface enriched with the hydrophobic tails and the glycerol groups buried inside. When in contact with water, the TG molecules at the interface orient the glycerol group towards the water phase and adopt a characteristic trident conformation. Water is shown to penetrate the TG layer thanks to the interaction with the oxygen atoms of the TG molecules, which acts as a pathway for water diffusion. The activation energy for the passage of water is found to be ≈9.5kBT at 310 K, showing that the layer is permeable to water diffusion.

What if we were able to watch on the computer screen how water, surfactants, and polymers come together to make up the liquid structure of formulated products, such as shampoos or laundry liquids?

In Part I, we reported all-atom, fully solvated molecular dynamics (MD) simulations of epigallocatechin-3-gallate (EGCG) binding to keratin. Herein, we report the second part of experimental investigation on EGCG binding to keratin using ultrafiltration and isothermal titration calorimetry (ITC). The thermodynamic equilibrium of EGCG binding to keratin has been quantitatively determined using ultrafiltration and high-performance liquid chromatography-UV/vis. The relationship confirms multilayer binding of EGCG to keratin which was observed in MD simulations. By combining the ultrafiltration and ITC data, the thermodynamic parameters of EGCG binding to keratin have been quantified. The obtained free energy of the first layer binding (ΔG=-6.37 kcal mol) is shown in excellent agreement with that obtained from computer simulations (ΔG=-6.20 kcal mol) presented in Part I. © 2013 American Institute of Chemical Engineers.

Nonspecific binding of small molecules to proteins influences transdermal permeation and intestinal absorption, yet understanding of the molecular and thermodynamic basis is still limited. In this study, we report all-atom, fully solvated molecular dynamics simulations of the thermodynamic characteristics of epigallocatechin-3-gallate (EGCG) binding keratin. Experimental validation is reported in Part II. Herein, 18 μs of simulation sampling was calculated. We show that the binding process is a combination of hydrophobic interaction, hydrogen bonding and aromatic interaction. The umbrella sampling technique was used to calculate the binding free energy of EGCG with keratin segments. By extracting EGCG from the keratin-EGCG complex using steered molecular dynamics, the rupture force was observed to be linearly related to the binding free energy. Multilayer binding of EGCG clusters to keratin has been shown. The binding free energy of -6.2 kcal mol obtained from the simulations was in excellent agreement with the experimental Part II. © 2013 American Institute of Chemical Engineers.

Monoglycerides and unsaturated fatty acids, naturally present in trace amounts in the stratum corneum (top layer of skin) lipid matrix, are commonly used in pharmaceutical, cosmetic and health care formulations. However, a detailed molecular understanding of how the oil additives get incorporated into the skin lipids from topical application and, once incorporated, how they affect the properties and integrity of the lipid matrix remains unexplored. Using ceramide 2 bilayers as skin lipid surrogates, we use a series of molecular dynamics simulations with six different natural oil ingredients at multiple concentrations to investigate the effect of the oils on the properties and stability of the bilayers. The six oils: monoolein, monostearin, monoelaidin, oleic acid, stearic acid and linoleic acid – all having the same length of the alkyl chain, C18, but a varying degree of saturation, allow us to systematically address the effect of unsaturation in the additives. Our results show that at low oil concentration (∼5%) the mixed bilayers containing any of the oils and ceramide 2 (CER2) become more rigid than pure CER2 bilayers due to more efficient lipid packing. Better packing also results in the formation of larger numbers of hydrogen bonds between the lipids, which occurs at the expense of the hydrogen bonds between lipids and water. The mixed bilayers with saturated or trans-unsaturated oils remain stable over the whole range of oil concentration. In contrast, the presence of the oils with at least one cis-double bond leads to bilayer instability and complete loss of bilayer structure at the oil content of about 50–65%. Two cis-double bonds in the lipid tail induce bilayer disruption at even lower concentration (∼30%). The mixed bilayers remain in the gel phase (without melting to a fluid phase) until the phase transition to a non-bilayer phase occurs. We also demonstrate that the stability of the bilayer strongly correlates with the order parameter of the lipid tails.

In this paper, we present protocols for simulating micelles using dissipative particle dynamics (and in principle molecular dynamics) that we expect to be appropriate for computing micelle properties for a wide range of surfactant molecules. The protocols address challenges in equilibrating and sampling, specifically when kinetics can be very different with changes in surfactant concentration, and with minor changes in molecular size and structure, even using the same force field parameters. We demonstrate that detection of equilibrium can be automated and is robust, for the molecules in this study and others we have considered. In order to quantify the degree of sampling obtained during simulations, metrics to assess the degree of molecular exchange among micellar material are presented, and the use of correlation times are prescribed to assess sampling and for statistical uncertainty estimates on the relevant simulation observables. We show that the computational challenges facing the measurement of the critical micelle concentration (CMC) are somewhat different for high and low CMC materials. While a specific choice is not recommended here, we demonstrate that various methods give values that are consistent in terms of trends, even if not numerically equivalent.

The stratum corneum is the uppermost layer of the skin and acts as a barrier to keep out contaminants and retain moisture. Understanding the molecular structure and behavior of this layer will provide guidance for optimizing its biological function. In this study we use a model mixture comprised of equimolar portions of ceramide NS (24:0), lignoceric acid, and cholesterol to model the effect of the addition of small amounts of oleic acid to the bilayer at 300 and 340 K. Five systems at each temperature have been simulated with concentrations between 0 and 0.1 mol % oleic acid. Our major finding is that subdiffusive behavior over the 200 ns time scale is evident in systems at 340 K, with cholesterol diffusion being enhanced with increased oleic acid. Importantly, cholesterol and other species diffuse faster when radial densities indicate nearest neighbors include more cholesterol. We also find that, with the addition of oleic acid, the bilayer midplane and interfacial densities are reduced and there is a 3% decrease in total thickness occurring mostly near the hydrophilic interface at 300 K with reduced overall density at 340 K. Increased interdigitation occurs independent of oleic acid with a temperature increase. Slight ordering of the long non-hydroxy fatty acid of the ceramide occurs near the hydrophilic interface as a function of the oleic acid concentration, but no significant impact on hydrogen bonding is seen in the chosen oleic acid concentrations.

We present atomistic molecular dynamics results for fully hydrated bilayers composed of ceramide NS-24:0, free fatty acid 24:0 and cholesterol, to address the effect of the different components in the stratum corneum (the outermost layer of skin) lipid matrix on its structural properties. Bilayers containing ceramide molecules show higher in-plane density and hence lower rate of passive transport compared to phospholipid bilayers. At physiological temperatures, for all composition ratios explored, the lipids are in a gel phase with ordered lipid tails. However, the large asymmetry in the lengths of the two tails of the ceramide molecule leads to a fluid like environment at the bilayer mid-plane. The lateral pressure profiles show large local variations across the bilayer for pure ceramide or any of the two component mixtures. Close to the skin composition ratio, the lateral pressure fluctuations are greatly suppressed, the ceramide tails from the two leaflets interdigitate significantly, the depression in local density at the inter-leaflet region is lowered, and the bilayer have lowered elastic moduli. This indicates that the observed composition ratio in the stratum corneum lipid layer is responsible for both the good barrier properties and the stability of the lipid structure against mechanical stresses., 14 pages, 17 figures

Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy profile of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.

The fatty acid oleic acid (OA) is known to modulate the structure of membranes, which forms the basis for a number of its important applications including its use as a therapeutic supplement to reduce the risk of cardiovascular disease, in molecule delivery systems such as liposomes, and as a skin permeability enhancer. While a number of studies have investigated the effect of OA on lipid membranes, our understanding of its mechanisms of action at the molecular level remains rudimentary. We have carried out molecular dynamics simulations using coarse-grained models to investigate the interactions of OA at a range of concentrations with a dipalmitoylphosphatidylcholine (DPPC) bilayer in the liquid-crystalline phase. We have also investigated the relative permeability of the bilayers to model hydrophilic and hydrophobic penetrants by means of chemical potential calculations. The results indicate that OA is able to disperse homogeneously into the bilayer at all concentrations without much perturbation. OA appears to slightly weaken the lateral forces between lipid headgroups, and as the concentration of OA increases this manifests itself as a slight decrease in the area compressibility modulus and a minor increase in the diffusion rate of the OA molecules. While the chemical potential profiles showed little or no variation as a function of OA concentration, the frequency of water permeation events was found to double, indicating some OA-induced permeability enhancement. The study suggests that physiological effects of OA are probably more subtle rather than via gross perturbation of the structure, or that its significant effects are restricted to more condensed membrane structures such as the gel phase.

The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0−0.6mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (≥0.4mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability.

Keratins are cytoskeletal proteins that hierarchically arrange into filaments, starting with the dimer sub-unit. They are integral to the structural support of cells, in skin, hair and nails. In skin, keratin is thought to play a critical role in conferring the barrier properties and elasticity of skin. In general, the keratin dimer is broadly described by a tri-domain structure: a head, a central rod and a tail. As yet, no atomistic-scale picture of the entire dimer structure exists; this information is pivotal for establishing molecular-level connections between structure and function in intermediate filament proteins. The roles of the head and tail domains in facilitating keratin filament assembly and function remain as open questions. To address these, we report results of molecular dynamics simulations of the entire epithelial human K1/K10 keratin dimer. Our findings comprise: (1) the first three-dimensional structural models of the complete dimer unit, comprising of the head, rod and tail domains; (2) new insights into the chirality of the rod-domain twist gained from analysis of the full domain structure; (3) evidence for tri-subdomain partitioning in the head and tail domains; and, (4) identification of the residue characteristics that mediate non-covalent contact between the chains in the dimer. Our findings are immediately applicable to other epithelial keratins, such as K8/K18 and K5/K14, and to intermediate filament proteins in general.\ud \ud

The bulk thermodynamic properties of proteins originate from a varied and complex combination of interactions. We propose a simple model for the formation of ordered two-dimensional aggregates based on the interactions between pairs of annexin V molecules. Simulations of this model are shown to reproduce the experimental observations of a honeycomb (p6) and a triangular (p3) crystalline phase. The simulations indicate that the transition between these two phases is first order. While this model is extremely simple in that it relies only on hard body and short-range directional interactions, it nevertheless captures the essential physics of the interactions between the protein molecules and reproduces the phase behavior observed in electron microscopy and atomic force microscopy experiments.

The bulk thermodynamic properties of membrane proteins originate from a complex combination of molecular interactions. We propose a simple model based on the pair interactions between a model membrane protein, annexin V. The experimental observations of a honeycomb (p6) and a triangular (p3) phase are successfully reproduced with Monte Carlo computer simulations. Grand canonical simulations and a newly developed "strip"-move constant pressure technique reveal the stability of a dilute fluid phase and a dense solid phase, not observed with the current experimental technology. While this model is extremely simple in that it relies only on hard-body and short-range directional interactions, it nevertheless captures the essential physics of the interactions between the protein molecules and reproduces the phase behavior observed in experiments.

We present a systematic, top-down, thermodynamic parametrization scheme for dissipative particle dynamics (DPD) using water-octanol partition coefficients, supplemented by water-octanol phase equilibria and pure liquid phase density data. We demonstrate the feasibility of computing the required partition coefficients in DPD using brute-force simulation, within an adaptive semi-automatic staged optimization scheme. We test the methodology by fitting to experimental partition coefficient data for twenty one small molecules in five classes comprising alcohols and poly-alcohols, amines, ethers and simple aromatics, and alkanes (i.e. hexane). Finally, we illustrate the transferability of a subset of the determined parameters by calculating the critical micelle concentrations of selected alkyl ethoxylate surfactants, in good agreement with reported experimental values., Comment: 12 pages, 4 figures, 7 tables, RevTeX 4.1

We report a numerical simulation of the phase diagram of a simple model for membrane proteins constrained to move in a plane. In analogy with the corresponding three dimensional models, the liquid-gas transition becomes metastable as the range of attraction decreases. Spontaneous crystallization happens much more readily in the two dimensional models rather than in their three dimensional counterparts., Revtex, 9 pages, 7 figures

Electromagnetic phenomena can be simulated by the dynamics of a mechanical system as long as the Hamiltonian of the electromagnetic and the mechanical systems coincide. In this paper we present a generalization of G.F. FitzGerald's pulleys and rubber-bands mechanical model for the interaction of electromagnetic waves with complex media. We show a direct analogy between the FitzGerald model and the electric vector potential formulation, at each stage of the extension of the original model: each mechanical observable has a unique correspondence in the vector potential formulation. This strict analogy allows further inductive developments of the mechanical model and extends the pedagogical importance of the original FitzGerald model. As a consequence very complex materials from the electromagnetic point of view, such as frequency dependent magneto dielectric materials are easily understood and implemented with simple modifications in the mechanical system. The condense node representation of the fie...

Although Enskog kinetic theory describes intermolecular collisional dynamics in terms of hard core molecular cross sections with inclusion of environmental crowding (excluded volume), more detailed analyses must incorporate the effects due to softness of the intermolecular potential and correlations of successive collisions. We present a simple model for the probability, pr(t), for a collision (defined as a velocity reversal) to occur at a time t after the last collision, that includes all the effects listed. Although the model incorporates correlated collisions, it does so only in the sense that such correlations affect pr(t), an intrinsically Markovian property since it carries memory only back to the last collision. We also examine the sign velocity autocorrelation function in order to identify the strictly Markovian contributions to the collisional dynamics.

We treat the competition between self-energy (single-micelle curvature preference) and interaction (interaggregate) effects on the evolution of micellar shapes and long-range ordering phase transitions in ternary systems of mixed surfactant and water. One surfactant prefers to satisfy the hydrophobic effect via formation of globular (positive curvature) micelles, whereas for the other we have in mind the phospholipids, for instance, which prefer to aggregate as planar bilayers. It follows that the preferred curvature in the ternary mixture case will depend sensitively on composition, i.e., on the relative numbers of the two surfactants. At high total concentrations of surfactant, however, the micellar shape is controlled as well by the relative efficiencies of packing aggregates of different curvature, independent of relative amphiphile mole numbers. By combining these self-energy and intermicellar interaction effects, then, we are able to generate “master” phase diagrams for the ternary systems, as a fun...

Iron binding to protein is common in biological processes of dioxygen transport, electron transfer as well as in stabilizing drug-protein complexes. α-Helix is the most prevalent secondary structure of proteins. In this study, Fe(2+) binding to α-helix has been studied by isothermal titration calorimetry (ITC) and explicitly solvated molecular dynamics (MD) simulation. Ferrous gluconate and α-helix-rich keratin are used for the ITC study and the results revealed followed one set of identical sites binding model. The MD simulations further revealed that only the acidic side-chain functional groups and η(2) (O,O) coordination modes are involved in the binding of Fe(2+) to α-helix. The ITC results also showed that the binding of ferrous gluconate to keratin was entropy driven and the higher the temperature, the stronger the binding free energy. The favorable entropy of Fe(2+) binding to keratin was attributed to the displacement of water molecules on the α-helix surface, and was confirmed via MD simulations. The most stable coordination states of Fe(2+) and α-helix were identified via simulation: Fe(2+) stacks between two glutamic acid side chain carboxylate groups, displacing water molecules. The binding free energies calculated using MD simulation and the theoretical values were in excellent agreement with the ITC results.

The outermost layer of skin, the stratum corneum (SC), comprises rigid corneocytes in a layered lipid matrix. Using atomistic simulations we find that the equilibrium phase of the SC lipids is inverse micellar. A model of the corneocyte is used to demonstrate that lamellar layering is induced by the patterned corneocyte wall. The inverse micellar phase is consistent with in vivo observations in the lacunar spaces and at the stratum granulosum - SC boundary region, and suggests a functional role in the lipid synthesis pathway in vivo., pdflatex 5 pages, 10 page supplementary material. Published Physical Review Letters. Added link to website with animations

We have developed a model for the interactions between keratin intermediate filaments based on self-consistent field theory. The intermediate filaments are represented by charged surfaces, and the disordered terminal domains of the keratins are represented by charged heteropolymers grafted to these surfaces. We estimate the system is close to a charge compensation point where the heteropolymer grafting density is matched to the surface charge density. Using a protein model with amino acid resolution for the terminal domains, we find that the terminal chains can mediate a weak attraction between the keratin surfaces. The origin of the attraction is a combination of bridging and electrostatics. The attraction disappears when the system moves away from the charge compensation point, or when excess small ions and/or NMF-representing free amino acids are added. These results are in concordance with experimental observations, and support the idea that the interaction between keratin filaments, and ultimately in part the elastic properties of the keratin-containing tissue, is controlled by a combination of the physico-chemical properties of the disordered terminal domains and the composition of the medium in the inter-filament region., Comment: 14 pages, 8 figures, 3 tables, RevTeX 4

Stochastic cage models require a choice for the cage variables suitable to describe the restoring forces generated by the solvent on the solute. A set of cage variables is introduced from the parametrization of the cage potential which is defined as the solute–solvent interaction energy considered as a function of the solute position for a fixed solvent configuration. This is an operative definition of cage variables that allows their identification at each time step of molecular dynamics simulations. Therefore, quantitative information about the equilibrium properties and the dynamics of cage variables can be extracted from molecular dynamics simulations. This procedure is applied to liquid argon near the triple point, in order to recognize the different processes contributing to the cage diffusion. The equilibrium distribution and the characteristic correlation times are derived as ingredients for the stochastic cage model developed in part II of the work.

By means of molecular dynamics simulations we have investigated increasing configurational ordering and decreasing particle mobility with increasing density ρ of a two-dimensional equilibrated liquid composed of soft discs. An equaltime correlation function h 2 (3) (0) which includes three-body, as well as twobody, correlations is introduced as a measure of structural order; this function is related to the dipole-induced-dipole equal-time correlation function h 2 (4) (0), and its sensitivity to structural order in the liquid is associated with the cancellation effect, the cancellation of the positive contribution of the two-body correlations by the negative contribution of the three-body correlations

We have developed both 10- and 2-site molecular dynamics simulation models of biological membranes, tested their ability to model various lipid phases, and to reproduce important membrane physical properties, particularly the lateral pressure profile which is critical in determining the phases adopted in lipid systems [1]. The novelty in these models lies predominantly in the way they capture shape anisotropy, and the realistic way in which electrostatic interactions are incorporated. Furthermore, through careful design, the 10-site model in particular is compatible with atomistic models, allowing multiscale simulations of membrane systems [2].In this presentation, the design philosophy and parameterisation procedures for these models will be described, together with their validation, with a particular focus on their lateral pressure profiles and phase behaviour. The application of these models in the context of multiscale simulations will then be considered. First, their use to calculate the permeability coefficients of small molecules through phospholipid bilayers, by combining molecular dynamics simulations with constraints, will be outlined [3]. Second, the effect of small molecules on membrane properties will be discussed, focusing particularly on antibacterials, which, it is postulated, may work through modifying the underlying physics of the membrane.[1] M. Orsi, D. Y. Haubertin, W. E. Sanderson and J. W. Essex, J. Phys. Chem. B, 2008, 112, 802-815.[2] J. Michel, M. Orsi and J. W. Essex, J. Phys. Chem. B, 2008, 112, 657-660.[3] M. Orsi, W.E. Sanderson and J.W. Essex, J. Phys. Chem. B, 2009, 113, 12019-12029.

Stratum corneum, the outermost layer of skin, consists of keratin filled rigid non-viable corneocyte cells surrounded by multilayers of lipids. The lipid layer is responsible for the barrier properties of the skin. We calculate the excess chemical potential and diffusivity of water as a function of depth in lipid bilayers with compositions representative of the stratum corneum using atomistic molecular dynamics simulations. The maximum in the excess free energy of water inside the lipid bilayers is found to be twice that of water in phospholipid bilayers at the same temperature. Permeability, which decreases exponentially with the free energy barrier, is reduced by several orders of magnitude as compared to with phospholipid bilayers. The average time it takes for a water molecule to cross the bilayer is calculated by solving the Smoluchowski equation in presence of the free energy barrier. For a bilayer composed of a 2:2:1 molar ratio of ceramide NS 24:0, cholesterol and free fatty acid 24:0 at 300K, we estimate the permeability P=3.7e-9 cm/s and the average crossing time \tau_{av}=0.69 ms. The permeability is about 30 times smaller than existing experimental results on mammalian skin sections., Comment: latex, 8 pages, 6 figures

We present an alternative vector potential formulation of Maxwell's equations derived upon introduction of a quantity related to the Hertz potential. Once space and time are discretized, within this formulation the electric field and vector potential components are condensed in the same point in the elementary cell. In three dimensions the formulation offers an alternative to finite-difference time-domain (FDTD) method; when reduced to a two-dimensional (2-D) problem, only two variables, instead of three, are necessary, implying a net memory saving of 1/3 with respect to FDTD.

Dimethylsulfoxide (DMSO) is an aprotic solvent that has the ability to induce cell fusion and cell differentiation and enhance the permeability of lipid membranes. It is also an effective cryoprotectant. Insights into how this molecule modulates membrane structure and function would be invaluable toward regulating the above processes and for developing chemical means for enhancing or hindering the absorption of biologically active molecules, in particular into or via the skin. We show here by means of molecular simulations that DMSO can induce water pores in dipalmitoyl-phosphatidylcholine bilayers and propose this to be a possible pathway for the enhancement of penetration of actives through lipid membranes. DMSO also causes the membrane to become floppier, which would enhance permeability, facilitate membrane fusion, and enable the cell membrane to accommodate osmotic and mechanical stresses during cryopreservation.

We report a numerical calculation of the melting point of NaCl. The solid–liquid transition was located by determining the point where the chemical potentials of the solid and liquid phases intersect. To compute these chemical potentials, we made use of free energy calculations. For the solid phase the free energy was determined by thermodynamic integration from the Einstein crystal. For the liquid phase two distinct approaches were employed: one based on particle insertion and growth using the Kirkwood coupling parameter, and the other involving thermodynamic integration of the NaCl liquid to a Lennard-Jones fluid. The latter approach was found to be significantly more accurate. The coexistence point at 1074 K was characterized by a pressure of –30±40 MPa and a chemical potential of –97.9±0.2kβT. This result is remarkably good as the error bounds on the pressure enclose the expected coexistence pressure of about 0.1 MPa (ambient). Using the Clausius–Clapyron relation, we estimate that dP/dT ≈3 MPa/K. This yields a melting point of 1064±14 K at ambient pressure, which encompasses the quoted range for the experimental melting point (1072.45–1074.4 K). The good agreement with the experimental melting-point data provides additional evidence that the Tosi–Fumi model for NaCl is quite accurate. Our study illustrates that the melting point of an ionic system can be calculated accurately by employing a judicious combination of free energy techniques. The techniques used in this work can be directly extended to more complex, charged systems.

A new approach for the solution of electromagnetic problems is presented and tested. The method is based of the discretization of Maxwell's equations, but it differs from the FDTD implementation in that it exploits a different scheme to model wave propagation. Vector and Scalar potential are used instead of the magnetic field, to propagate the electric field. This implementation provides a condensed node representation for the electric field, offers a natural way to treat interfaces, and allows modeling of Debye relaxation media, avoiding convolution. Additionally a mechanical analog can be devised.

The introduction of the scalar and vector potentials allows us to rewrite Maxwell's equations with a different formalism. Upon discretization, we exploit the advantages of the condensed node representation of the fields, resulting in lower grid dispersion, memory and computational time saving. Numerical examples are presented to validate the technique in two and three dimensions.

We propose an extension of the law of corresponding states that can be applied to systems - such as colloidal suspensions - that have widely different ranges of attractive interactions. We argue that, for such systems, the ``reduced'' second virial coefficient is a convenient parameter to quantify the effective range of attraction. This procedure allows us to give a simple definition of the effective range of attraction of potentials with different functional forms. The advantage of the present approach is that it allows us to estimate the relative location of the liquid-vapor and solid-fluid coexistence curves exclusively on basis of the knowledge of the pair-potential., REVTeX, 5 pages, 2 figures

The dense lipid bilayers at the outer surface of the skin represent the primary barrier to molecules penetrating the human skin. One approach to overcome this barrier, with promising applications in administering medicinal drugs to the body, is to employ chemical permeability enhancers. How these enhancers, such as dimethylsulfoxide (DMSO), exert their effect at the molecular level is only partly understood. We present molecular dynamics simulations to elucidate the interaction of DMSO with bilayers of ceramide 2, the most abundant lipid in the skin. The DMSO molecules are found to weaken the impermeable crystalline bilayers, and even to cause a transition to a fluidized phase at high DMSO concentrations. This is consistent with the experimental evidence that a substantial concentration of DMSO is required to enhance the permeability of the skin. Trans-membrane pores are created using a constraint technique, and the free energy change during pore formation is calculated. High DMSO concentrations yield archetypal hydrophilic pores, i.e. the membrane edge surrounding the pore is lined with lipid head groups, while in pure water we observe the formation of hydrophobic pores, i.e. the lipid tails are exposed at the membrane edge. Although hydrophobic pores are commonly envisaged to contain water, we find that nanometer-sized pores are actually empty. The origins and consequences of these vapour pores are discussed.

The phase behavior of colloid-polymer mixtures, and of solutions of globular proteins, is often interpreted in terms of a simple model of hard spheres with short-ranged attraction. While such a model yields a qualitative understanding of the generic phase diagrams of both colloids and proteins, it fails to capture one important difference: the model predicts fluid-fluid phase separation in the metastable regime below the freezing curve. Such demixing has been observed for globular proteins, but for colloids it appears to be pre-empted by the appearance of a gel. In this paper, we study the effect of additional long-range attractions on the phase behavior of spheres with short-ranged attraction. We find that such attractions can shift the (metastable) fluid-fluid critical point out of the gel region. As this metastable critical point may be important for crystal nucleation, our results suggest that long-ranged attractive forces may play an important role in the crystallization of globular proteins. However, in colloids, where refractive index matching is often used to switch off long-ranged dispersion forces, gelation is likely to inhibit phase separation., EURO-LATEX, 6 pages, 2 figures

A link between molecular and mesoscopic simulations for water-soluble polymers is made using the potential of mean force (PMF) method. Mesoscale parameters are adjusted to match selected thermodynamic quantities such as the monomer second virial coefficient or the limiting slope of the monomer adsorption isotherm, which are computed directly from atomistic PMFs. The method is illustrated by computing the bulk and surface interaction parameters (chi parameters in self-consistent field theory) for the adsorption of ethylene oxide (EO) and propylene oxide (PO) polymers from aqueous solution onto silica.

This double-blind study assesses the therapeutic efficacy and the safety of oral treatment with phosphatidylserine (BC-PS) vs placebo (300 mg/day for 6 months) in a group of geriatric patients with cognitive impairment. A total of 494 elderly patients (age between 65 and 93 years), with moderate to severe cognitive decline, according to the Mini Mental State Examination and Global Deterioration Scale, were recruited in 23 Geriatric or General Medicine Units in Northeastern Italy. Sixty-nine patients dropped out within the 6-month trial period. Patients were examined just before starting therapy, and 3 and 6 months thereafter. The efficacy of treatment compared to placebo was measured on the basis of changes occurring in behavior and cognitive performance using the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test. Statistically significant improvements in the phosphatidylserine-treated group compared to placebo were observed both in terms of behavioral and cognitive parameters. In addition, clinical evaluation and laboratory tests demonstrated that BC-PS was well tolerated. These results are clinically important since the patients were representative of the geriatric population commonly met in clinical practice.