Article pubs.acs.org/Langmuir
Oleic Acid Phase Behavior from Molecular Dynamics Simulations J. Joel Janke, W. F. Drew Bennett, and D. Peter Tieleman* Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, 2500 University Drive, Calgary, AB T2N 1N4, Canada S Supporting Information *
ABSTRACT: Fatty acid aggregation is important for a number of diverse applications: from origins of life research to industrial applications to health and disease. Experiments have characterized the phase behavior of oleic acid mixtures, but the molecular details are complex and hard to probe with many experiments. Coarse-grained molecular dynamics computer simulations and free energy calculations are used to model oleic acid aggregation. From random dispersions, we observe the aggregation of oleic acid monomers into micelles, vesicles, and oil phases, depending on the protonation state of the oleic acid head groups. Worm-like micelles are observed when all the oleic acid molecules are deprotonated and negatively charged. Vesicles form spontaneously if significant amounts of both neutral and negative oleic acid are present. Oil phases form when all the fatty acids are protonated and neutral. This behavior qualitatively matches experimental observations of oleic acid aggregation. To explain the observed phase behavior, we use umbrella sampling free energy calculations to determine the stability of individual monomers in aggregates compared to water. We find that both neutral and negative oleic acid molecules prefer larger aggregates, but neutral monomers prefer negatively charged aggregates and negative monomers prefer neutral aggregates. Both neutral and negative monomers are most stable in a DOPC bilayer, with implications on fatty acid adsorption and cellular membrane evolution. Although the CG model qualitatively reproduces oleic acid phase behavior, we show that an updated polarizable water model is needed to more accurately predict the shift in pKa for oleic acid in model bilayers.
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INTRODUCTION
Molecular dynamics simulations have been used extensively to study surfactant aggregation.12−18 Oleic acid in DPPC bilayers was investigated with coarse-grained simulations, showing that it did not have a large effect on the structure or permeability of DPPC bilayers.19 Similarly, oleic acid and 2hydroxyoleic acid simulated with an atomistic model in DPPC bilayers did not cause significant bilayer perturbations.20 Oleate self-aggregation was simulated at a number of different concentrations, although without any neutral oleic acid.21 Oleic acid triple layers were studied with atomistic simulations, finding fast diffusion of monomers across the aggregate, although oleate was not included in this system.22 Morrow and co-workers investigated small lauric acid aggregates using constant pH simulations with atomistic models, showing a positive shift in the pKa in aggregates.23,24 Using constant pH simulations and the MARTINI model, we recently showed qualitatively similar results for the titration of oleic acid in different aggregates.25 Here we used standard molecular dynamics simulations with the coarse-grained (CG) MARTINI force field26 to characterize oleic acid and oleate aggregation behavior. We varied the oleic acid (OAOH) to oleate (OA−1) ratio and concentration to assess the aggregation in different pH conditions, with all neutral OA to mimic low pH, all charged for high pH, and mixed at or near the pKa of the OAs. To quantitatively describe aggregate
Fatty acids are simple but crucial biomolecules and are important industrially due to their natural abundance. Free fatty acids are important in health and disease and are involved in many inflammation related diseases.1 Free fatty acids show antimicrobial activity,2 with potential applications in agriculture, cosmetics, and medicine.3 They are cytotoxic to human cells, with possible applications in cancer treatment.4,5 Oleic acid vesicles have been used as a model for protocell membranes due to their natural abundance and ability to self-aggregate into vesicles.6 Fatty acids have been suggested for drug delivery and are in general good models for pH-dependent targeted drug delivery.7 These are but some of the applications of fatty acids, suggesting a more fundamental understanding of their aggregation behavior is needed. Oleic acid (OA) is a long chain fatty acid with a hydrophobic 18-carbon tail (cis-9 double bond) and a polar carboxylic acid headgroup. In solution, free fatty acids display complex phase behavior, which is dependent on the pH of the system. The pKa of long chain fatty acid monomers has not been determined due to aggregation even at very low concentrations but should be close to other short tail fatty acids, which is ∼4.8.8 Compared to a monomer the pKa shifts to higher values when aggregated, up to 8 in aggregated fatty acid vesicles9 and 7.5 in a phospholipid bilayer.10 The deprotonation/protonation state of the system directly affects the aggregation behavior, with micelles at high pH values (>10), vesicles at intermediate values (8−10), and oil phases at low pH (
