Accurate modeling of ionic surfactants at high concentration.

Molecular dynamics (MD) simulation is a useful tool for simulating formulations of surfactant mixtures from first-principles, which can be used to predict surfactant morphology and other industrially relevant thermodynamic properties. However, the surfactant structure is sensitive to the parameters used in MD simulations, and in the absence of extensive validation against experimental data, it is often not obvious a priori which range of parameter sets to choose. In this work, we compare the performance of ion parameters implemented in nonpolarizable classical MD simulations, and its effect on simulations of an idealized solution of sodium dodecyl sulfate (SDS). We find that previous artifacts reported in simulations of larger SDS constructs are a direct consequence of using parameters that poorly model ionic interactions at high concentration. Using osmotic pressure and/or other thermodynamic properties measured at finite concentration, such as Kirkwood-Buff integrals, is shown to be the most cost-effective means to validate and parametrize existing force fields. Our findings highlight the importance of optimizing intermolecular parameters for simulations of systems with a high local concentration, which may be applicable in other contexts, such as in molecular crowding, hotspot mapping, protein folding, and modeling pH effects.

Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats.

The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5-20 mmol/kg. Ethanol was eliminated most rapidly, at 7.9 mmol/kgh. Secondary alcohols (2-propanol-d7, 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol) were eliminated with first order kinetics at doses of 5-10 mmol/kg, and the corresponding ketones were formed and slowly eliminated with zero or first order kinetics. The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmol/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols. The Michaelis kinetic constants from in vitro studies (pH 7.3, 37 °C) with isolated rat liver enzyme were used to calculate the expected relative rates of metabolism in rats. The rates of elimination generally increased with increased activity of ADH, but a maximum rate of 6±1 mmol/kg h was observed for the best substrates, suggesting that ADH activity is not solely rate-limiting. Because secondary alcohols only require one NAD(+) for the conversion to ketones whereas primary alcohols require two equivalents of NAD(+) for oxidation to the carboxylic acids, it appears that the rate of oxidation of NADH to NAD(+) is not a major limiting factor for metabolism of these alcohols, but the rate-limiting factors are yet to be identified.

Rationalization of reduced penetration of drugs through ceramide gel phase membrane.

Since computing resources have advanced enough to allow routine molecular simulation studies of drug molecules interacting with biologically relevant membranes, a considerable amount of work has been carried out with fluid phospholipid systems. However, there is very little work in the literature on drug interactions with gel phase lipids. This poses a significant limitation for understanding permeation through the stratum corneum where the primary pathway is expected to be through a highly ordered lipid matrix. To address this point, we analyzed the interactions of p-aminobenzoic acid (PABA) and its ethyl (benzocaine) and butyl (butamben) esters with two membrane bilayers, which differ in their fluidity at ambient conditions. We considered a dioleoylphosphatidylcholine (DOPC) bilayer in a fluid state and a ceramide 2 (CER2, ceramide NS) bilayer in a gel phase. We carried out unbiased (100 ns long) and biased z-constraint molecular dynamics simulations and calculated the free energy profiles of all molecules along the bilayer normal. The free energy profiles converged significantly slower for the gel phase. While the compounds have comparable affinities for both membranes, they exhibit penetration barriers almost 3 times higher in the gel phase CER2 bilayer. This elevated barrier and slower diffusion in the CER2 bilayer, which are caused by the high ordering of CER2 lipid chains, explain the low permeability of the gel phase membranes. We also compared the free energy profiles from MD simulations with those obtained from COSMOmic. This method provided the same trends in behavior for the guest molecules in both bilayers; however, the penetration barriers calculated by COSMOmic did not differ between membranes. In conclusion, we show how membrane fluid properties affect the interaction of drug-like molecules with membranes.

Predicting proton titration in cationic micelle and bilayer environments.

Knowledge of the protonation behavior of pH-sensitive molecules in micelles and bilayers has significant implications in consumer product development and biomedical applications. However, the calculation of pKa's in such environments proves challenging using traditional structure-based calculations. Here we apply all-atom constant pH molecular dynamics with explicit ions and titratable water to calculate the pKa of a fatty acid molecule in a micelle of dodecyl trimethylammonium chloride and liquid as well as gel-phase bilayers of diethyl ester dimethylammonium chloride. Interestingly, the pKa of the fatty acid in the gel bilayer is 5.4, 0.4 units lower than that in the analogous liquid bilayer or micelle, despite the fact that the protonated carboxylic group is significantly more desolvated in the gel bilayer. This work illustrates the capability of all-atom constant pH molecular dynamics in capturing the delicate balance in the free energies of desolvation and Coulombic interactions. It also shows the importance of the explicit treatment of ions in sampling the protonation states. The ability to model dynamics of pH-responsive substrates in a bilayer environment is useful for improving fabric care products as well as our understanding of the side effects of anti-inflammatory drugs.

Origins of microstructural transformations in charged vesicle suspensions: the crowding hypothesis.

It is observed that charged unilamellar vesicles in a suspension can spontaneously deflate and subsequently transition to form bilamellar vesicles, even in the absence of externally applied triggers such as salt or temperature gradients. We provide strong evidence that the driving force for this deflation-induced transition is the repulsive electrostatic pressure between charged vesicles in concentrated suspensions, above a critical effective volume fraction. We use volume fraction measurements and cryogenic transmission electron microscopy imaging to quantitatively follow both the macroscopic and microstructural time-evolution of cationic diC18:1 DEEDMAC vesicle suspensions at different surfactant and salt concentrations. A simple model is developed to estimate the extent of deflation of unilamellar vesicles caused by electrostatic interactions with neighboring vesicles. It is determined that when the effective volume fraction of the suspension exceeds a critical value, charged vesicles in a suspension can experience "crowding" due to overlap of their electrical double layers, which can result in deflation and subsequent microstructural transformations to reduce the effective volume fraction of the suspension. Ordinarily in polydisperse colloidal suspensions, particles interacting via a repulsive potential transform into a glassy state above a critical volume fraction. The behavior of charged vesicle suspensions reported in this paper thus represents a new mechanism for the relaxation of repulsive interactions in crowded situations.