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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.

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.

Free energy prediction of ligand binding to macromolecules using explicit solvent molecular dynamics (MD) simulations is computationally very expensive. Recently, we reported a linear correlation between the binding free energy obtained via umbrella sampling (US) versus the rupture force from steered molecular dynamics (SMD) simulations for epigallocatechin-3-gallate (EGCG) binding to α-helical-rich keratin. This linear correlation suggests a potential route for fast free energy predictions using SMD alone. In this work, the generality of the linear correlation is further tested for several ligands interacting with the α-helical motif of keratin. These molecules have significantly varying properties, i.e., octanol/water partition coefficient (log P), and/or overall charges (oleic acid, catechin, Fe(2+), citric acid, hydrogen citrate, dihydrogen citrate, and citrate). Using the constant loading rate of our previous study of the keratin-EGCG system, we observe that the linear correlation for keratin-EGCG can be extended to other uncharged molecules where interactions are governed by hydrogen bonds and/or a combination of hydrogen bonds and hydrophobic forces. For molecules where interactions with the keratin helix are governed primarily by electrostatics between charged molecules, a second, alternative linear correlation model is derived. While further investigations are needed to expand the molecular space and build a fully predictive model, the current approach represents a promising methodology for fast free energy predictions based on short SMD simulations (requiring picoseconds to nanoseconds of sampling) for defined biomolecular systems.

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.

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 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.

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.

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.

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.

Complex formulations such as emulsions are widely used for enhancing the solubility and delivery of functional ingredients. Many experiments have been reported to evaluate how functional chemical compounds partition between phases of complex structures of micelles and emulsions. A great challenge is to predict these thermodynamic properties of wide chemicals. Here we explore a multi-scale approach for in-silico prediction of the partition coefficient in two steps: At first a molecular dynamic simulation (MD’s) is performed to determine the micelle and emulsion structure of the simulated system. In the second stage the predicted micellar and emulsion structure file is processed in COSMOtherm to determine the Gibbs free energy profile and so the partition coefficient of the whole structure of the aggregate. We report initial progress in predicting the micelle-water partition of a wide chemical space in a model SDS micelle system. The predicted partition coefficient is then compared to published experimental data in order to evaluate the accuracy and reliability of the methodology. Further work will be carried for real-world emulsion systems to achieve a good agreement between calculated and experimental data.