Influence of Small Fluorophilic and Lipophilic Organic Molecules on

Article pubs.acs.org/JPCB

Influence of Small Fluorophilic and Lipophilic Organic Molecules on Dipalmitoylphosphatidylcholine Bilayers Martin Brehm, Ghulam Saddiq, Tobias Watermann, and Daniel Sebastiani* Institut für ChemieTheoretische Chemie, Martin-Luther-Universität Halle-Wittenberg, Von-Danckelmann-Platz 4, 06120 Halle (Saale), Germany ABSTRACT: In this study, we investigate the effect of a series of additive molecules with different types of philicities on the structure and dynamics of dipalmitoylphosphatidylcholine (DPPC) bilayers. To this aim, we performed extensive force field molecular dynamics simulations of the systems, using our recently developed perfluoroalkane force field. We found that addition of perfluoro-n-decane and fluorotelomer alcohol at 323 K leads to a phase transition of the membrane from liquid crystalline to the gel phase, whereas the addition of n-decane and partially fluorinated n-decane leaves the liquid crystalline phase intact. The systems in the gel phase show a significantly reduced diffusivity for both DPPC and additive molecules. The addition of nonfluorinated and partially fluorinated n-decane even leads to an increased DPPC diffusivity. While nonfluorinated n-decane and partially fluorinated n-decane are found mainly in the middle of the bilayer, perfluoro-n-decane penetrates significantly deeper into the membrane leaflet. Fluorotelomer alcohol is found almost exclusively inside the leaflet, with its hydroxyl groups forming a strong hydrogen bond network to the ester oxygen atoms in the head group of DPPC. A slight increase in temperature by only 10 K is already sufficient to dynamically overcome this hydrogen bond network, such that no phase transition occurs in that case.

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inertness, and high fluidity.10,11 The fundamental properties and potential applications of fluorinated amphiphiles have been reviewed in the literature.5,6 It is generally perceived that fluorine exerts only a moderate steric influence relative to hydrogen in organic compounds,12 but the electronegativity of fluorine can have significant electronic influences. Amphiphiles with short fluorinated chains (n(CF2) ⩽ 8) are considered to be acceptable in clinical applications. In addition, highly fluorinated amphiphiles have multiple applications in materials science5,13,14 as well as in the biomedical field, often involving colloidal systems stabilized by monomolecular films of fluorinated amphiphiles. They could potentially find applications as blood substitutes13,15−18 and lung surfactant replacements.19−22 As examples, fluorinated alcohols such as hexafluoro-2propanol (HFIP) and trifluoroethanol (TFE) are not considered sensu stricto as fluorous media.23 However, the presence of one or more fluoroalkyl groups introduces specific properties to fluorinated alcohols compared to those that are nonfluorinated. They have high ionizing power24 and an acidic character.25 They are strong hydrogen bond donors26 and poor nucleophiles.27 The properties of fluorinated alcohols have been exploited in physical organic chemistry,27 in the

INTRODUCTION Perfluorinated n-alkanes represent an interesting and special class of molecules due to their specific and unusual properties. As a result of the special nature of the C−F bond, they are considerably more hydrophobic than lipids, but they are not lipophilic either, which allows for interesting applications both in materials science and in biochemistry. Despite their structural similarity to hydrocarbons, these fluorocarbons have high thermal stability and chemical inactivity.1 Although strong intramolecular forces are present due to the C−F bond, the weak polarizability of the fluorinated chains results in low intermolecular or van der Waals interactions.2 Minimal intermolecular interactions, coupled with the bulkiness and rigidity of the C−F chains, lead to higher density, higher melting points, lower surface tension, low refractive indices, lower boiling points, and surface spreading of fluorocarbon compounds in comparison with hydrocarbons.3 Perfluorinated compounds (PFCs) have numerous applications for medical purposes as oxygen-carrier fluids,4,5 in purification or polymerization,4 and as lubricants.6 PFCs are especially interesting due to their phase separation behavior in hydrocarbon environments.7 The versatility of their applications can be attributed to the strength of the C−F covalent bond, which results in physicochemical properties that are distinct from those of traditional hydrocarbon-based systems.8,9 Fluorinated amphiphiles are attractive due to their unique properties, such as combined hydrophobicity and lipophobicity10 and high gas-dissolving capacity, chemical and biological © XXXX American Chemical Society

Received: July 3, 2017 Revised: August 16, 2017 Published: August 16, 2017 A

DOI: 10.1021/acs.jpcb.7b06520 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry B Table 1. Systems Studied system pure H10

H5F5

F10

FTOH

FTOH 333 K

FTOH 4:1

composition

mixing ratio

72 DPPC 2189 H2O 72 DPPC 2189 H2O 12 CH3(CH2)8CH3 72 DPPC 2189 H2O 12 CH3(CH2)4(CF2)4CF3 72 DPPC 2189 H2O 12 CF3(CF2)8CF3 72 DPPC 2189 H2O 12 CF3(CF2)7(CH2)2OH 72 DPPC 2189 H2O 12 CF3(CF2)7(CH2)2OH 72 DPPC 2189 H2O 18 CF3(CF2)7(CH2)2OH

simulation temp (K)

simulation time (ns)

323

69.3

6:1

323

311.2

6:1

323

301.0

6:1

323

301.5

6:1

323

268.9

6:1

333

301.9

4:1

323

279.4

stabilization of radical cations,28 and for their effect on the conformation of proteins and peptides.29 Among fluorinated alcohols, fluorotelomer alcohols (FTOHs) play a significant role in studies of atmospheric chemistry. FTOHs are linear fluorinated alcohols with the formula CnF2n+1C2H4OH (n = 2, 4, 6, ...).30,31 FTOH molecules have physicochemical properties similar to those of perfluoro-n-alkanes. For this reason, this study investigates the fluorotelomer alcohol CF3(CF2)7(CH2)2OH, which possesses a hydroxyl group of weak acidity in a normal aqueous environment and is not strongly affected by pH. The choice of phospholipids as a constituent in model membranes is important in describing the partitioning in a real biological system. A prominent phospholipid is the dipalmitoylphosphatidylcholine (DPPC) bilayer, for which a phase transition at 41 °C has been reported.32 DPPC is one of the constituents of the pulmonary surfactant found in lung alveoli.33 DPPC bilayers are well characterized,34,35 and are often used as models of the outer cell membrane leaflet. A characteristic feature of the DPPC is the gel−liquid crystalline phase transition, which occurs at a temperature Tm (melting temperature) that is dependent on the bilayer properties and solution conditions.36 In the gel phase (